CYP450 Upregulation

50-18-0

CMSMOCZEIVJLDB-UHFFFAOYNA-N

CMSMOCZEIVJLDB-UHFFFAOYSA-N

Cyclophosphamide

2H-1,3,2-Oxazaphosphorin-2-amine, N,N-bis(2-chloroethyl)tetrahydro-, 2-oxide (.+-.)-Cyclophosphamide (RS)-Cyclophosphamide 2-[Bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorin 2-oxide 2H-1,3,2-Oxazaphosphorin, 2-amine, N,N-bis((2-chloroethyl)tetrahydro-, 2-oxide 2H-1,3,2-Oxazaphosphorin-2-amine, N,N-bis(2-chloroethyl)tetrahydro-,2-oxide 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide Bis(2-chloroethyl)phosphoramide cyclic propanolamide ester ciclofosfamida Claphene Cycloblastin Cyclophosphamid Cyclophosphamidum Cyclophosphan Cyclophosphane Cyclostin Cytophosphan Cytoxan Endoxan Endoxan R Endoxana Endoxanal Endoxan-Asta Endoxane Enduxan Genoxal Mitoxan N,N-Bis(2-chloroethyl)-N',O-propylenephosphoric acid ester diamide N,N-Bis(β-chloroethyl)-N',O-trimethylenephosphoric acid ester diamide NCI C04900 NSC 26271 Procytox Semdoxan Sendoxan Senduxan Zyklophosphamid 2-(Bis(2-chloroethyl)amino)-2H-1,3,2-oxazaphosphorine 2-oxide 1-Bis(2-chloroethyl)amino-1-oxo-2-aza-5-oxaphosphoridin 2-(Bis(2-chloroethyl)amino)tetrahydro-2H-1,3,2-oxazophosphorine 2-oxide N,N-Bis(beta-chloroethyl)-N',O-propylenephosphoric acid ester diamide N,N-Bis(beta-chloroethyl)-N',O-trimethylenephosphoric acid ester diamide BRN 0011744 Cyclophosphanum Cyclophosphoramide Cytophosphane N,N-Di(2-chloroethyl)-N,O-propylene-phosphoric acid ester diamide EINECS 200-015-4 4-Hydroxy-cyclophosphan-mamophosphatide NCI-C04900 Occupation, cyclophosphamide exposure Phosphorodiamidic acid, N,N-bis(2-chloroethyl)-N'-(3-hydroxypropyl)-, intramol. ester RCRA waste number U058 (+-)-Cyclophosphamide Ciclophosphamide Lyophilized cytoxan Cyklofosfamid N,N-Bis-(beta-chloraethyl)-N',O-propylen-phosphorsaeure-ester-diamid UNII-6UXW23996M NSC-26271 D,L-Cyclophosphamide

DTXSID5020364

107-02-8

HGINCPLSRVDWNT-UHFFFAOYSA-N

Acrolein

2-Propenal 2-Propen-1-al 2-Propen-1-one acrilaldehido Acroleina Acrylaldehyd Acrylaldehyde Acrylic aldehyde Allyl aldehyde Aqualin Magnacide B Magnacide H NSC 8819 Prop-2-en-1-al Propenal UN 1092

DTXSID5020023

3778-73-2

HOMGKSMUEGBAAB-UHFFFAOYNA-N

HOMGKSMUEGBAAB-UHFFFAOYSA-N

Ifosfamide

Isophosphamide 2H-1,3,2-Oxazaphosphorin-2-amine, N,3-bis(2-chloroethyl)tetrahydro-, 2-oxide (.+-.)-Ifosfamide 2H-1,3,2-Oxazaphosphorine, 3-(2-chloroethyl)-2-[(2-chloroethyl)amino]tetrahydro-, 2-oxide 3-(2-Chloroethyl)-2-(2-chloroethylamino)tetrahydro-2H-1,3,2-oxaazaphosphorin 2-oxide 3-(2-Chloroethyl)-2-(2-chloroethylamino)tetrahydro-2H-1,3,2-oxazaphosphorin 2-oxide 3-(2-Chloroethyl)-2-(2-chloroethylamino)tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide Asta Z 4942 Holoxan Holoxan 1000 Ifomide Ifosfamid ifosfamida Ifosfomide Ifosphamide Iphosphamide Isoendoxan Isofosfamide Mitoxana Naxamide NSC 109724

DTXSID7020760

60-35-5

DLFVBJFMPXGRIB-UHFFFAOYSA-N

Acetamide

Acetamid acetamida Acetic acid amide Acetimidic acid Ethanamide Ethanimidic acid Methanecarboxamide NSC 25945

DTXSID7020005

103-90-2

RZVAJINKPMORJF-UHFFFAOYSA-N

Acetaminophen

4-Acetamidophenol APAP Paracetamol 4-hydroxyacetanilide Acetamide, N-(4-hydroxyphenyl)- 4-(Acetylamino)phenol 4-(N-Acetylamino)phenol 4-Acetaminophenol 4'-Hydroxyacetanilide Abensanil Acetagesic Acetalgin ACETAMIDE, N-(4-HYDROXYPHENYL) Acetaminofen Acetanilide, 4'-hydroxy- ACETANILIDE, 4-HYDROXY- Algotropyl Alvedon Anaflon Apamide Banesin Ben-u-ron Bickie-mol Biocetamol Cetadol Citramon P Claratal Clixodyne Dafalgan Daphalgan Dial-a-gesic Disprol Doliprane Dolprone Dymadon Efferalgan Endophy Febrilex Febrilix Febro-Gesic Febrolin Fepanil Finimal Gattaphen T Gelocatil Gutte Enteric Homoolan Jin Gang Lestemp Liquagesic Lonarid Lyteca Syrup Minoset Momentum N-(4-Hydroxyphenyl)acetamide N-Acetyl-4-aminophenol N-Acetyl-4-hydroxyaniline N-Acetyl-p-aminophenol Napafen Naprinol Nobedon NSC 109028 NSC 3991 Ortensan p-(Acetylamino)phenol p-Aceaminophenol Pacemol p-Acetamidophenol p-Acetoaminophen P-ACETYLAMINOPHENOL Paldesic panadeine Panadol Panadol Actifast Panadol Extend Panaleve Panasorb Panodil Paracetamol DC Paracetamole Parageniol Paramol Paraspen Parelan Pasolind N Perfalgan Phenaphen Phendon p-Hydroxyacetanilide Prodafalgan Puerxitong Pyrinazine Resfenol Resprin Rhodapop NCR Salzone Tabalgin Tachipirina Tempanal Tralgon Tylenol TylolHot Valadol Valgesic Vermidon Vick Pyrena

DTXSID2020006

968-81-0

VGZSUPCWNCWDAN-UHFFFAOYSA-N

Acetohexamide

Benzenesulfonamide, 4-acetyl-N-[(cyclohexylamino)carbonyl]- 1-(p-Acetylbenzenesulfonyl)-3-cyclohexylurea 1-[(p-Acetylphenyl)sulfonyl]-3-cyclohexylurea Acetohexamid acetohexamida Dimelin Dimelor Dymelor Gamadiabet Hypoglicil Metaglucina Minoral N-(p-Acetylphenylsulfonyl)-N'-cyclohexylurea Ordimel Tsiklamid Urea, 1-[(p-acetylphenyl)sulfonyl]-3-cyclohexyl-

DTXSID7020007

67-66-3

HEDRZPFGACZZDS-UHFFFAOYSA-N

Chloroform

Trichloromethane Methane, trichloro- CARBON TRICHLORIDE Chloroforme cloroformo Formyl trichloride Methane trichloride Methane,trichloro- NSC 77361 Trichloroform UN 1888

DTXSID1020306

110-00-9

YLQBMQCUIZJEEH-UHFFFAOYSA-N

Furan

Divinylene oxide furanne Furfuran Oxacyclopentadiene Tetrole UN 2389

DTXSID6020646

7429-90-5

XAGFODPZIPBFFR-UHFFFAOYSA-N

AZDRQVAHHNSJOQ-UHFFFAOYSA-N

Aluminum

Aisin Metal Fiber Al 050P-H24 ALC Fine Alcan XI 1391 Almi-Paste SSP 303AR Aloxal 3010 Alpaste 00-0506 Alpaste 0100M Alpaste 0100MA Alpaste 0100M-C Alpaste 0200M Alpaste 0200T Alpaste 0230M Alpaste 0230T Alpaste 0241M Alpaste 0300M Alpaste 0500M Alpaste 0539X Alpaste 0620MS Alpaste 0625TS Alpaste 0638-70C Alpaste 0700M Alpaste 0780M Alpaste 0900M Alpaste 100M Alpaste 100MS Alpaste 100MSR Alpaste 1100M Alpaste 1100MA Alpaste 1100N Alpaste 1100NA Alpaste 1109MA Alpaste 1109MC Alpaste 1200M Alpaste 1200T Alpaste 1260MS Alpaste 1500MA Alpaste 1700NL Alpaste 1810YL Alpaste 1830YL Alpaste 1900M Alpaste 1900XS Alpaste 1950M Alpaste 1950N Alpaste 210N Alpaste 2172EA Alpaste 2173 Alpaste 240T Alpaste 241M Alpaste 417 Alpaste 46-046 Alpaste 4-621 Alpaste 4919 Alpaste 50-63 Alpaste 50-635 Alpaste 51-148B Alpaste 51-231 Alpaste 5205N Alpaste 5207N Alpaste 52-509 Alpaste 52-568 Alpaste 5301N Alpaste 5302N Alpaste 53-119 Alpaste 5422NS Alpaste 54-452 Alpaste 54-497 Alpaste 54-542 Alpaste 55-516 Alpaste 55-519 Alpaste 55-574 Alpaste 5620NS Alpaste 5630NS Alpaste 5640NS Alpaste 56-501 Alpaste 5650NS Alpaste 5653NS Alpaste 5654NS Alpaste 5680N Alpaste 5680NS Alpaste 60-600 Alpaste 60-760 Alpaste 60-768 Alpaste 62-356 Alpaste 6340NS Alpaste 6370NS Alpaste 6390NS Alpaste 640NS Alpaste 65-388 Alpaste 66NLB Alpaste 710N Alpaste 7130N Alpaste 7160N Alpaste 7160NS Alpaste 725N Alpaste 740NS Alpaste 7430NS Alpaste 7580NS Alpaste 7620NS Alpaste 7640NS Alpaste 7670M Alpaste 7670NS Alpaste 7675NS Alpaste 7679NS Alpaste 7680N Alpaste 7680NS Alpaste 76840NS Alpaste 7730N Alpaste 7770N Alpaste 7830N Alpaste 8004 Alpaste 8080N Alpaste 8260NAR Alpaste 891K Alpaste 91-0562 Alpaste 92-0592 Alpaste 93-0595 Alpaste 93-0647 Alpaste 94-2315 Alpaste 95-0570 Alpaste 96-0635 Alpaste 96-2104 Alpaste 97-0510 Alpaste 97-0534 Alpaste AW 520B Alpaste AW 612 Alpaste AW 9800 Alpaste F 795 Alpaste FM 7680K Alpaste FX 440 Alpaste FX 910 Alpaste FZ 0534 Alpaste FZU 40C Alpaste G Alpaste HR 8801 Alpaste HS 2 Alpaste J Alpaste K 9800 Alpaste MC 666 Alpaste MC 707 Alpaste MF 20 Alpaste MG 01 Alpaste MG 1000 Alpaste MG 1300 Alpaste MG 500 Alpaste MG 600 Alpaste MH 6601 Alpaste MH 8801 Alpaste MH 9901 Alpaste MR 7000 Alpaste MR 9000 Alpaste MS 630 Alpaste N 1700NL Alpaste NS 7670 Alpaste O 100N Alpaste O 2130 Alpaste O 300M Alpaste P 0100 Alpaste P 1950 Alpaste S Alpaste SAP 110 Alpaste SAP 414P Alpaste SAP 550N Alpaste SCR 5070 Alpaste TCR 2020 Alpaste TCR 2060 Alpaste TCR 2070 Alpaste TCR 3010 Alpaste TCR 3030 Alpaste TCR 3040 Alpaste TCR 3130 Alpaste TD 200T Alpaste UF 500 Alpaste WB 0230 Alpaste WD 500 Alpaste WJP-U 75C Alpaste WX 0630 Alpaste WX 7830 Alpaste WXA 7640 Alpaste WXM 0630 Alpaste WXM 0650 Alpaste WXM 0660 Alpaste WXM 1415 Alpaste WXM 1440 Alpaste WXM 5422 Alpaste WXM 760b Alpaste WXM 7640 Alpaste WXM 7675 Alpaste WXM-T 60B Alpaste WXM-U 75 Alpaste WXM-U 75C Altop X Aluchrome Ultrafin Super Alumat 1600 Alumet H 30 aluminio Aluminium Aluminium Flake Aluminum 27 Aluminum atom Aluminum element Aluminum Flake PCF 7620 Aluminum granules ALUMINUM METAL/GRANULE ALUMINUM PASTE ALUMINUM PIGMENT ALUMINUM TURNINGS Alumi-paste 640NS Alumipaste 91-0562 Alumipaste 98-1822T Alumipaste AW 620 Alumipaste CR 300 Alumipaste GX 180A Alumipaste GX 201A Alumipaste HR 7000 Alumipaste HR 850 Alumipaste MG 11 Alumipaste MH 8801 Aquamet NPW 2900 Aquapaste 205-5 Aquasilver LPW Astroflake 40 Astroflake Black N 020 Astroflake Black N 070 Astroflake LG 40 Astroflake LG 70 Astroflake Silver N 040 Astroshine NJ 1600 Astroshine T 8990 Atomizalumi VA 200 C.I. PIGMENT METAL 1 Chromal IV Chromal X Decomet 1001/10 Decomet 2018/10 Decomet High Gloss Al 1002/10 Ecka AS 081 Eckart 9155 Eterna Brite 301-1 Eterna Brite 601-1 Eterna Brite 651-1 Eterna Brite EBP 251PA Eterna Brite Primier 251PA Ferro FX 53-038 Friend Color F 500GR-W Friend Color F 500WT Friend Color F 700RE-W Friend Color F 701RE-W Hi Print 60T High Print 60T Hisparkle HS 2 Hydro Paste 8726 Hydrolac WHH 2153 Hydrolan 3560 Hydrolux Reflexal 100 Hydroshine WS 1001 JISA 51010P Kryal Z Lansford 243 LE Sheet 800 Leafing Alpaste LG-H Silver 25 Lunar Al-V 95 Metallux 161 Metallux 2154 Metallux 2192 Metalure Metalure 55350 Metalure L 55350 Metalure L 59510 Metalure W 2001 Metapor Metasheen 1800 Metasheen HR 0800 Metasheen KM 100 Metasheen KM 1000 Metasheen Slurry 1807 Metasheen Slurry 1811 Metasheen Slurry KM 100 Metax G Metax S Mirror Glow 1000 Mirror Glow 600 Mirrorsheen Noral Aluminium Noral Ink Grade Aluminium Obron 10890 Offset FM 4500 Puratronic Reflexal 145 Reynolds 400 Reynolds 4-301 Reynolds 4-591 Reynolds 667 SAP 260PW-HS SAP-FM 4010 SBC 516-20Z Scotchcal 7755SE Serumekku Setanium 50MIS-H8 Siberline ET 2025 Siberline ST 21030E1 Silvar A Silver VT 522 Silverline SSP 353 Silvex 793-20C Sparkle Silver 3141ST Sparkle Silver 3500 Sparkle Silver 3641 Sparkle Silver 5000AR Sparkle Silver 516AR Sparkle Silver 5242AR Sparkle Silver 5245AR Sparkle Silver 5271AR Sparkle Silver 5500 Sparkle Silver 5745 Sparkle Silver 7000AR Sparkle Silver 7005AR Sparkle Silver 7500 Sparkle Silver 960-25E1 Sparkle Silver E 1745AR Sparkle Silver L 1526AR Sparkle Silver Premier 751 Sparkle Silver SS 3130 Sparkle Silver SS 5242AR Sparkle Silver SS 5588 Sparkle Silver SSP 132AR Special PCR 507 Splendal 6001BG Spota Mobil 801 SSP 760-20C Stapa Aloxal PM 2010 Stapa Aloxal PM 3010 Stapa Aloxal PM 4010 Stapa Hydrolac BG 8n.1 Stapa Hydrolac BGH Chromal X Stapa Hydrolac PM Chromal VIII Stapa Hydrolac W 60NL Stapa Hydrolac WH 16 Stapa Hydrolac WH 66NL Stapa Hydrolux 2192 Stapa Hydrolux 8154 Stapa IL Hydrolan 2192-55900G Stapa Metallic R 607 Stapa Metallux 1050 Stapa Metallux 211 Stapa Metallux 212 Stapa Metallux 2196 Stapa Metallux 274 Stapa Mobilux 181 Stapa Offset 3000 Stapa PV 10 Stapa VP 46432G Starbrite 2100 Super Fine 18000 Super Fine 22000 Supramex 2022 Toyo Aluminum 02-0005 Toyo Aluminum 93-3040 Transmet K 102HE Tufflake 3645 Tufflake 5843 UN 1396 US Aluminum 809 Valimet H 2 Valimet H 3 White Silver 7080N White Silver 7130N

DTXSID3040273

7440-43-9

BDOSMKKIYDKNTQ-UHFFFAOYSA-N

Cadmium

Cadimium CADMIUM BLUE CADMIUM, IN PLATTEN, STANGEN, BROCKEN,KOERNER

DTXSID1023940

7439-97-6

QSHDDOUJBYECFT-UHFFFAOYSA-N

Mercury

Liquid silver Mercure MERCURIC METAL TRIPLE DISTILLED mercurio Mercury element Quecksilber Quicksilver UN 2024 UN 2809

DTXSID1024172

7440-61-1

JFALSRSLKYAFGM-UHFFFAOYSA-N

Uranium

Uranium, isotope of mass 238 238U Element UN 2979 (DOT) Uranium I

DTXSID1042522

7440-38-2

RQNWIZPPADIBDY-UHFFFAOYSA-N

Arsenic

As Arsenic black ARSENIC METAL arsenico Grey arsenic UN 1558

DTXSID4023886

7440-22-4

BQCADISMDOOEFD-UHFFFAOYSA-N

Silver

Ag Nanopaste NPS-J 90 Ag Sphere 2 Ag-C-GS Algaedyn Arctic Silver 3 Argentum Astroflake 5 Carey Lea silver Colloidal silver Dotite XA 208 Du Pont 4943 ECM 100AF4810 Enlight 600 Enlight silver plate 600 Epinall Finesphere SVND 102 Fordel DC FP 5369-502 Jelcon SH 1 Jungindai Takasago 300 KS (metal) LCP 1-19SFS Metz 3000-1 Nanomelt AGC-A Nanomelt Ag-XA 301 Nanomelt Ag-XF 301 Nanomelt Ag-XF 301H Nanopaste NPS-J 90 Perfect Silver Puff Silver X 1200 RT 1710S-C1 SD (metal) Shell Silver Silbest E 20 Silbest F 20 Silbest J 18 Silbest TC 12 Silbest TC 20E Silbest TC 25A Silbest TCG 1 Silbest TCG 7 Silcoat AgC 103 Silcoat AgC 2011 Silcoat AgC 209 Silcoat AgC 2190 Silcoat AgC 222 Silcoat AgC 2411 Silcoat AgC 74T Silcoat AgC-A Silcoat AgC-AO Silcoat AgC-B Silcoat AgC-BO Silcoat AgC-D Silcoat AgC-G Silcoat AgC-GS Silcoat AgC-L Silcoat AgC-O Silcoat GS Silcoat RF 200 Silflake 135 Silsphere 514 Silver atom Silver element Silver Flake 1 Silver Flake 25 Silver Flake 52 Silver Flake 7A SILVER FLAKES Silver metal Silvest TCG 11N Technic 299 Technic 450 Techno Alpha 175

DTXSID4024305

7439-96-5

PWHULOQIROXLJO-UHFFFAOYSA-N

Manganese

Colloidal manganese Cutaval Manganese element Manganese fulleride Manganese metal alloy Manganese-55 manganeso

DTXSID2024169

7440-02-0

PXHVJJICTQNCMI-UHFFFAOYSA-N

Nickel

Carbonyl 255 Carbonyl Ni 123 Carbonyl Ni 283 Carbonyl Nickel 123 Carbonyl Nickel 283 Carbonyl Nickel 287 Cerac N 2003 CNS 10 Micron Exmet 4 Ni X-4/0 Fibrex P Incofoam Nickel element NICKEL ROUND ANODES Nicrobraz LM:BNi 2 Ni-Flake 95 Novamet 123 Novamet 4SP Novamet 4SP10 Novamet 525 Novamet CNS 400 Novamet HCA 1 Novamet NI 255 Raney nickel Raney nickel 2800 UN 1325 UN 2881

DTXSID2020925

7440-66-6

HCHKCACWOHOZIP-UHFFFAOYSA-N

Zinc

Zn Asarco L 15 C.I. Pigment Black 16 Merrillite NC-Zinc Rheinzink Stapa TE Zinc AT UF (metal) UN 1436 Zinc dust Zinc Dust 3 Zinc Dust 500 mesh Zinc Dust LS 2 Zinc Dust MCS Zinc Flakes GTT ZINC METAL ZINC MOSSY ZINC STRIP ZINC, MOSSY Zincsalt GTT

DTXSID7035012

CHEBI:26208

CHEBI polyunsaturated fatty acid

MP:0003674

MP oxidative stress

GO:0034440

GO lipid oxidation

WIKI increased

Cyclophosphamide

2024-06-04T21:30:55

Acrolein

2017-08-15T09:55:59

2021-09-28T08:23:20

Ifosfamide

2024-06-14T13:48:06

Acetaminophen

2016-11-29T18:42:26

Chloroform

2016-11-29T18:42:27

furan

2020-05-01T14:35:22

Platinum

2022-02-04T14:36:54

Aluminum

2022-02-04T14:42:11

Cadmium

2017-10-25T08:33:12

Mercury

2016-11-29T18:42:19

Uranium

2021-08-05T14:28:50

Arsenic

2021-04-27T00:15:21

Silver

2022-02-03T11:20:11

Manganese

2022-02-04T14:47:23

Nickel

2022-02-04T14:47:59

Zinc

2022-02-04T15:05:00

nanoparticles

2016-12-21T09:40:06

9606

NCBI Homo sapiens

976298

NCBI Primates sp. BOLD:AAA0001

WikiUser_26

ApacheUser rodents

10095

NCBI mice

10116

NCBI rats

WCS_9606

common toxicological species humans

9685

NCBI cats

WikiUser_6

ApacheUser fish

WikiUser_17

mammals

WCS_9606

common toxicological species human

CYP450 Upregulation

Molecular

Cytochrome P450 (CYP450) enzymes are a class of membrane-bound hemo-protiens that work to detoxify various small exogenous xenobiotics and endogenous substances through oxidation, reduction, or hydrolysis, also referred to as Phase 1 metabolism <cite>(Zhao et al., 2021, Gilani & Cassagnol, 2023</cite>). CYP450 enzymes have various locations within organs such as the liver, kidney, and the intestine but these enzymes can most prominently be found in the liver. On a cellular level, CYP450 is expressed within eukaryotes cells and some prokaryotes, mainly in the mitochondria or the endoplasmic reticulum <cite>(Gilani & Cassagnol, 2023)</cite>.  Typically but not always, the endoplasmic reticulum CYP450 mostly metabolizes exogenous substances such as drugs, whereas the mitochondrial enzymes interact with endogenous process such as steroid hormone metabolism and fatty acid regulation. There are 18 mammalian CYP450 families which encode for 57 genes found in the human genome (<cite>Nebert et al., 2013</cite>). As such many isoforms in the CYP450 family exist and exhibit different metabolic activities, substrate affinities, conformation, and expression. In addition, most CYP enzyme expression depends on a transcription inducing substrate for upregulation or downregulation. However, in an attempt to metabolize compounds, occasionally CYP450 enzymes can bioactivate a substrate into a more toxic metabolite, such as turning vinyls into vinyl epoxides <cite>(Guengerich, 2003</cite>). **Please note that the Cell term and Organ term only allow for one selection in the traning AOP wiki

<ul> <li> P450 Spectral assay:  Total CYP450 enzyme detection and activity can be measured through its spectral properties and has been outlined by Guengerich et al., (2009). In this paper, the spectral determination of total CYP450 is completed by monitoring the reaction of CYP450 hemeprotein with carbon monoxide via spectrophotometry. The carbon monoxide CYP450 complex creates spectrum with at a maximum wavelength of ~450 nm and an extinction coefficient of 91, 000 M-1 cm -1 which corresponds to the cysteine thiolate axial ligand connection to the heme iron present in the enzyme<cite> (Johnston et al., 2008, </cite><cite>Guengerich et al. 2009., Omura and Sato 1964)</cite>. </li> <li> Immunochemical assays: The detection of many CYP450 enzymes has been discovered by obtaining microsomal fractions from various animals including primates and humans <cite>(Uehara et al., 2014, Nakanishi et al., 2011, Uehara et al., 2010, Uehara et al., 2011</cite>). A notable study outlined the use of cynomolgus monkey small intestine microsomal fractions to identify different types of CYP450's<cite> (Uehara et al., 2014)</cite>. The enzymes once separated via SDS PAGE were reacted with primary anti-human antibody corresponding to multiple CYP's of interest followed by secondary antibody and visualized via chemiluminescence. This technique is known as Western blotting which allows for the visualization of CYP450 upregulation or downregulation when compared to a control by comparison of chemiluminescent protein band intensity<cite> (Mahmood and Yang., 2012)</cite>.  </li> <li>Mass spectroscopy : Although in most studies CYP450 is not detected via analytical instruments such as the LC-MS/MS or GC-MS/MS, metabolites and substrates of these enzymes have been detected using mass spectroscopy <cite>(Nguyen et al., 2020, Behera et al., 2013, Jiang et al., 2022, Oh et al., 2015)</cite>. After incubation with a stressor/ substrate, the metabolites can be extracted and separated via liquid or gas chromatography then the chemical composition extrapolated from the resulting mass to charge ratio obtained by the tandem mass spectroscopy.</li> </ul> There are also other methods such as knockout experiments and mRNA assays in animals but those typically target specific CYP's!

<ul> <li>D: Taxonomic applicability In all studies gathered, the taxonomic applicability is quite wide spanning most eukaryotes including humans, plants, and rats <cite>(Uehara et al., 2014, Nakanishi et al., 2011, Uehara et al., 2010, Uehara et al., 2011, Zhao et al., 2021, Gilani & Cassagnol, 2023)</cite>.</li> <li>E: Life stages: The domain of applicability for life stages is all life stages. </li> <li>F: Sex applicability: The domain of applicability for sex is both males and females.</li> </ul>

High Mixed

High

All life stages

High High Behera D, Pattem R, Kumar MS, Gudi GS. Utility of a column-switching LC/MS/MS method in cytochrome P450 inhibition assays using human liver microsomes. Drug Metabol Drug Interact. Gilani, B., Cassagnol, M. (2023) Biochemistry, Cytochrome P450.  Guengerich, P., (2003). Cytochrome P450 oxidations in the generation of reactive electrophiles: epoxidation and related reactions, Archives of Biochemistry and Biophysics, 409(1),  59-71 Jiang F, Zhang C, Lu Z, Liu J, Liu P, Huang M, Zhong G., (2022) Simultaneous absolute protein quantification of seven cytochrome P450 isoforms in rat liver microsomes by LC-MS/MS-based isotope internal standard method. Front Pharmacol.  Johnston WA, Huang W, De Voss JJ, Hayes MA, Gillam EM. (2008)Quantitative whole-cell cytochrome P450 measurement suitable for high-throughput application. J Biomol Screen. 13(2):135-41.  Mahmood T, Yang PC. (2012)Western blot: technique, theory, and trouble shooting.  N Am J Med Sci. 2014(9):429-34.  Nebert DW, Wikvall K, Miller WL. (2013)  Human cytochromes P450 in health and disease. Philos Trans R Soc Lond B Biol Sci Nguyen V, Espiritu M, Elbarbry F.  (2020) Development and validation of a sensitive and specific LC–MS/MS cocktail assay for CYP450 enzymes: Application to study the effect of catechin on rat hepatic CYP activity. Biomedical Chromatography.  Oh HA, Lee H, Kim D, Jung BH. (2017) Development of GC-MS based cytochrome P450 assay for the investigation of multi-herb interaction. Anal Biochm. 15;519:71-83.  Tsuneo Omura, Ryo Sato, (1964) The Carbon Monoxide-binding Pigment of Liver Microsomes: I. EVIDENCE FOR ITS HEMOPROTEIN NATURE, Journal of Biological Chemistry, 239 (7) 2370-2378 Uehara S, Murayama N, Yamazaki H, Uno Y. (2010) A novel CYP2A26 identified in cynomolgus monkey liver metabolizes coumarin. Xenobiotica 40:621–9. Uehara S, Murayama N, Nakanishi Y, Zeldin DC, Yamazaki H, Uno Y. (2011) Immunochemical detection of cytochrome P450 enzymes in liver microsomes of 27 cynomolgus monkeys. J Pharmacol Exp Ther. 2011;339:654–61 Uehara S, Murayama N, Nakanishi Y, Nakamura C, Hashizume T, Zeldin DC, Yamazaki H, Uno Y. (2014) Immunochemical detection of cytochrome P450 enzymes in small intestine microsomes of male and female untreated juvenile cynomolgus monkeys. Xenobiotica.  Zhao, M., Ma, J., Li, M., Zhang, Y., Jiang, B., Zhao, X., Huai, C., Shen, L., Zhang, N., He, L., & Qin, S. (2021). Cytochrome P450 Enzymes and Drug Metabolism in Humans. International journal of molecular sciences, 22(23)  AOPWiki 2024-06-03T02:55:31

2024-06-20T21:01:31

Oxidative Stress

Molecular

Oxidative stress is defined as an imbalance in the production of reactive oxygen species (ROS) and antioxidant defenses. High levels of oxidizing free radicals can be very damaging to cells and molecules within the cell (Pizzino et al., 2017; Sharifi-Rad et al., 2020; Jena et al., 2023).  As a result, the cell has important defense mechanisms to protect itself from ROS. For example, Nrf2 is a transcription factor and master regulator of the oxidative stress response. During periods of oxidative stress, Nrf2-dependent changes in gene expression are important in regaining cellular homeostasis (Nguyen, et al. 2009) and can be used as indicators of the presence of oxidative stress in the cell. In addition to the directly damaging actions of ROS, cellular oxidative stress also changes cellular activities on a molecular level. Redox sensitive proteins have altered physiology in the presence and absence of ROS, which is caused by the oxidation of sulfhydryls to disulfides (2SH àSS) on neighboring amino acids (Antelmann and Helmann 2011). Importantly Keap1, the negative regulator of Nrf2, is regulated in this manner (Itoh, et al. 2010). ROS also undermine the mitochondrial defense system from oxidative damage. The antioxidant systems consist of superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase, as well as antioxidants such as α-tocopherol and ubiquinol, or antioxidant vitamins and minerals including vitamin E, C, carotene, lutein, zeaxanthin, selenium, and zinc (Fletcher, 2010). The enzymes, vitamins and minerals catalyze the conversion of ROS to non-toxic molecules such as water and O2. However, these antioxidant systems are not perfect and endogenous metabolic processes and/or exogenous oxidative influences can trigger cumulative oxidative injuries to the mitochondria, causing a decline in their functionality and efficiency, which further promotes cellular oxidative stress (Balasubramanian, 2000; Ganea & Harding, 2006; Guo et al., 2013; Karimi et al., 2017). However, an emerging viewpoint suggests that ROS-induced modifications may not be as detrimental as previously thought, but rather contribute to signaling processes (Foyer et al., 2017).  Protection against oxidative stress is relevant for all tissues and organs, although some tissues may be more susceptible. For example, the brain possesses several key physiological features, such as high O2 utilization, high polyunsaturated fatty acids content, presence of autooxidable neurotransmitters, and low antioxidant defenses as compared to other organs, that make it highly susceptible to oxidative stress (Halliwell, 2006; Emerit and al., 2004; Frauenberger et al., 2016). Sources of ROS Production Direct Sources: Direct sources involve the deposition of energy onto water molecules, breaking them into active radical species. When ionizing radiation hits water, it breaks it into hydrogen (H*) and hydroxyl (OH*) radicals by destroying its bonds. The hydrogen will create hydroxyperoxyl free radicals (HO2*) if oxygen is available, which can then react with another of itself to form hydrogen peroxide (H2O2) and more O2 (Elgazzar and Kazem, 2015). Antioxidant mechanisms are also affected by radiation, with catalase (CAT) and peroxidase (POD) levels rising as a result of exposure (Seen et al. 2018; Ahmad et al. 2021). Indirect Sources: An indirect source of ROS is the mitochondria, which is one of the primary producers in eukaryotic cells (Powers et al., 2008).  As much as 2% of the electrons that should be going through the electron transport chain in the mitochondria escape, allowing them an opportunity to interact with surrounding structures. Electron-oxygen reactions result in free radical production, including the formation of hydrogen peroxide (H2O2) (Zhao et al., 2019). The electron transport chain, which also creates ROS, is activated by free adenosine diphosphate (ADP), O2, and inorganic phosphate (Pi) (Hargreaves et al. 2020; Raimondi et al. 2020; Vargas-Mendoza et al. 2021). The first and third complexes of the transport chain are the most relevant to mammalian ROS production (Raimondi et al., 2020). The mitochondria have its own set of DNA and it is a prime target of oxidative damage (Guo et al., 2013). ROS are also produced through nicotinamide adenine dinucleotide phosphate oxidase (NOX) stimulation, an event commenced by angiotensin II, a product/effector of the renin-angiotensin system (Nguyen Dinh Cat et al. 2013; Forrester et al. 2018). Other ROS producers include xanthine oxidase, immune cells (macrophage, neutrophils, monocytes, and eosinophils), phospholipase A2 (PLA2), monoamine oxidase (MAO), and carbon-based nanomaterials (Powers et al. 2008; Jacobsen et al. 2008; Vargas-Mendoza et al. 2021).

Oxidative Stress. Direct measurement of ROS is difficult because ROS are unstable. The presence of ROS can be assayed indirectly by measurement of cellular antioxidants, or by ROS-dependent cellular damage. Listed below are common methods for detecting the KE, however there may be other comparable methods that are not listed <ul> <li>Detection of ROS by chemiluminescence (https://www.sciencedirect.com/science/article/abs/pii/S0165993606001683)</li> <li>Detection of ROS by chemiluminescence is also described in OECD TG 495 to assess phototoxic potential.</li> <li>Glutathione (GSH) depletion. GSH can be measured by assaying the ratio of reduced to oxidized glutathione (GSH:GSSG) using a commercially available kit (e.g., http://www.abcam.com/gshgssg-ratio-detection-assay-kit-fluorometric-green-ab138881.html). </li> <li>TBARS. Oxidative damage to lipids can be measured by assaying for lipid peroxidation using TBARS (thiobarbituric acid reactive substances) using a commercially available kit. </li> <li>8-oxo-dG. Oxidative damage to nucleic acids can be assayed by measuring 8-oxo-dG adducts (for which there are a number of ELISA based commercially available kits),or  HPLC, described in Chepelev et al. (Chepelev, et al. 2015).</li> </ul> Molecular Biology: Nrf2. Nrf2’s transcriptional activity is controlled post-translationally by oxidation of Keap1. Assay for Nrf2 activity include: <ul> <li>Immunohistochemistry for increases in Nrf2 protein levels and translocation into the nucleus</li> <li>Western blot for increased Nrf2 protein levels</li> <li>Western blot of cytoplasmic and nuclear fractions to observe translocation of Nrf2 protein from the cytoplasm to the nucleus</li> <li>qPCR of Nrf2 target genes (e.g., Nqo1, Hmox-1, Gcl, Gst, Prx, TrxR, Srxn), or by commercially available pathway-based qPCR array (e.g., oxidative stress array from SABiosciences)</li> <li>Whole transcriptome profiling by microarray or RNA-seq followed by pathway analysis (in IPA, DAVID, metacore, etc.) for enrichment of the Nrf2 oxidative stress response pathway (e.g., Jackson et al. 2014)</li> <li>OECD TG422D describes an ARE-Nrf2 Luciferase test method</li> <li>In general, there are a variety of commercially available colorimetric or fluorescent kits for detecting Nrf2 activation</li> </ul>   <table border="1" cellpadding="1" cellspacing="1"> <tbody> <tr> <td>Assay Type & Measured Content</td> <td>Description</td> <td>Dose Range Studied</td> <td> Assay Characteristics (Length / Ease of use/Accuracy) </td> </tr> <tr> <td> ROS Formation in the Mitochondria assay (Shaki et al., 2012) </td> <td>“The mitochondrial ROS measurement was performed flow cytometry using DCFH-DA. Briefly, isolated kidney mitochondria were incubated with UA (0, 50, 100 and 200 μM) in respiration buffer containing (0.32 mM sucrose, 10 mM Tris, 20 mM Mops, 50 μM EGTA, 0.5 mM MgCl2, 0.1 mM KH2PO4 and 5 mM sodium succinate) [32]. In the interval times of 5, 30 and 60 min following the UA addition, a sample was taken and DCFH-DA was added (final concentration, 10 μM) to mitochondria and was then incubated for 10 min. Uranyl acetate-induced ROS generation in isolated kidney mitochondria were determined through the flow cytometry (Partec, Deutschland) equipped with a 488-nm argon ion laser and supplied with the Flomax software and the signals were obtained using a 530-nm bandpass filter (FL-1 channel). Each determination is based on the mean fluorescence intensity of 15,000 counts.”</td> <td>0, 50, 100 and 200 μM of Uranyl Acetate</td> <td> Long/ Easy High accuracy </td> </tr> <tr> <td> Mitochondrial Antioxidant Content Assay Measuring GSH content (Shaki et al., 2012)</td> <td>“GSH content was determined using DTNB as the indicator and spectrophotometer method for the isolated mitochondria. The mitochondrial fractions (0.5 mg protein/ml) were incubated with various concentrations of uranyl acetate for 1 h at 30 °C and then 0.1 ml of mitochondrial fractions was added into 0.1 mol/l of phosphate buffers and 0.04% DTNB in a total volume of 3.0 ml (pH 7.4). The developed yellow color was read at 412 nm on a spectrophotometer (UV-1601 PC, Shimadzu, Japan). GSH content was expressed as μg/mg protein.”</td> <td> 0, 50, 100, or 200 μM Uranyl Acetate </td> <td> </td> </tr> <tr> <td> H2O2 Production Assay Measuring H2O2 Production in isolated mitochondria (Heyno et al., 2008)</td> <td>“Effect of CdCl2 and antimycin A (AA) on H2O2 production in isolated mitochondria from potato. H2O2 production was measured as scopoletin oxidation. Mitochondria were incubated for 30 min in the measuring buffer (see the Materials and Methods) containing 0.5 mM succinate as an electron donor and 0.2 µM mesoxalonitrile 3‐chlorophenylhydrazone (CCCP) as an uncoupler, 10 U horseradish peroxidase and 5 µM scopoletin.” (</td> <td> 0, 10, 30  μM Cd2+ 2  μM antimycin A</td> <td> </td> </tr> <tr> <td> Flow Cytometry ROS & Cell Viability (Kruiderig et al., 1997)</td> <td>“For determination of ROS, samples taken at the indicated time points were directly transferred to FACScan tubes. Dih123 (10 mM, final concentration) was added and cells were incubated at 37°C in a humidified atmosphere (95% air/5% CO2) for 10 min. At t 5 9, propidium iodide (10 mM, final concentration) was added, and cells were analyzed by flow cytometry at 60 ml/min. Nonfluorescent Dih123 is cleaved by ROS to fluorescent R123 and detected by the FL1 detector as described above for Dc (Van de Water 1995)”</td> <td> </td> <td> Strong/easy medium</td> </tr> <tr> <td> DCFH-DA Assay Detection of hydrogen peroxide production (Yuan et al., 2016) </td> <td> Intracellular ROS production was measured using DCFH-DA as a probe. Hydrogen peroxide oxidizes DCFH to DCF. The probe is hydrolyzed intracellularly to DCFH carboxylate anion. No direct reaction with H2O2 to form fluorescent production.    </td> <td>0-400 µM</td> <td> Long/ Easy High accuracy </td> </tr> <tr> <td> H2-DCF-DA Assay Detection of superoxide production (Thiebault et al., 2007) </td> <td>This dye is a stable nonpolar compound which diffuses readily into the cells and yields H2-DCF. Intracellular OH or ONOO- react with H2-DCF when cells contain peroxides, to form the highly fluorescent compound DCF, which effluxes the cell. Fluorescence intensity of DCF is measured using a fluorescence spectrophotometer.</td> <td>0–600 µM</td> <td> Long/ Easy High accuracy </td> </tr> <tr> <td>CM-H2DCFDA Assay</td> <td>**Come back and explain the flow cytometry determination of oxidative stress from Pan et al. (2009)**</td> <td> </td> <td> </td> </tr> </tbody> </table> Direct Methods of Measurement <table cellspacing="0" class="Table" style="border-collapse:collapse; width:623px"> <tbody> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:141px"> Method of Measurement  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:151px"> References  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:255px"> Description  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:76px"> OECD-Approved Assay </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px"> Chemiluminescence  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> (Lu, C. et al., 2006;  Griendling, K. K., et al., 2016) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px"> ROS can induce electron transitions in molecules, leading to electronically excited products. When the electrons transition back to ground state, chemiluminescence is emitted and can be measured. Reagents such as uminol and lucigenin are commonly used to amplify the signal.  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"> No   </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px"> Spectrophotometry  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> (Griendling, K. K., et al., 2016) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px"> NO has a short half-life. However, if it has been reduced to nitrite (NO2-), stable azocompounds can be formed via the Griess Reaction, and further measured by spectrophotometry.  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"> No </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px"> Direct or Spin Trapping-Based Electron Paramagnetic Resonance (EPR) Spectroscopy  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> (Griendling, K. K., et al., 2016) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px"> The unpaired electrons (free radicals) found in ROS can be detected with EPR, and is known as electron paramagnetic resonance. A variety of spin traps can be used.  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"> No </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px"> Nitroblue Tetrazolium Assay  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> (Griendling, K. K., et al., 2016) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px"> The Nitroblue Tetrazolium assay is used to measure O2•– levels. O2•– reduces nitroblue tetrazolium (a yellow dye) to formazan (a blue dye), and can be measured at 620 nm.  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"> No </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px"> Fluorescence analysis of dihydroethidium (DHE) or Hydrocyans  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> (Griendling, K. K., et al., 2016) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px"> Fluorescence analysis of DHE is used to measure O2•– levels. O2•–  is reduced to O2 as DHE is oxidized to 2-hydroxyethidium, and this reaction can be measured by fluorescence. Similarly, hydrocyans can be oxidized by any ROS, and measured via fluorescence.  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"> No </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px"> Amplex Red Assay  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> (Griendling, K. K., et al., 2016) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px"> Fluorescence analysis to measure extramitochondrial or extracellular H2O2 levels. In the presence of horseradish peroxidase and H2O2, Amplex Red is oxidized to resorufin, a fluorescent molecule measurable by plate reader.  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"> No </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px"> Dichlorodihydrofluorescein Diacetate (DCFH-DA)  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> (Griendling, K. K., et al., 2016) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px"> An indirect fluorescence analysis to measure intracellular H2O2 levels. H2O2 interacts with peroxidase or heme proteins, which further react with DCFH, oxidizing it to dichlorofluorescein (DCF), a fluorescent product.  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"> No </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px"> HyPer Probe  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> (Griendling, K. K., et al., 2016) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px"> Fluorescent measurement of intracellular H2O2 levels. HyPer is a genetically encoded fluorescent sensor that can be used for in vivo and in situ imaging.  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"> No </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px"> Cytochrome c Reduction Assay  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> (Griendling, K. K., et al., 2016) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px"> The cytochrome c reduction assay is used to measure O2•– levels. O2•–  is reduced to O2 as ferricytochrome c is oxidized to ferrocytochrome c, and this reaction can be measured by an absorbance increase at 550 nm.  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"> No </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px"> Proton-electron double-resonance imagine (PEDRI) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> (Griendling, K. K., et al., 2016) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px"> The redox state of tissue is detected through nuclear magnetic resonance/magnetic resonance imaging, with the use of a nitroxide spin probe or biradical molecule.  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"> No </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px"> Glutathione (GSH) depletion  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> (Biesemann, N. et al., 2018)  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px"> A downstream target of the Nrf2 pathway is involved in GSH synthesis. As an indication of oxidation status, GSH can be measured by assaying the ratio of reduced to oxidized glutathione (GSH:GSSG) using a commercially available kit (e.g., <a href="http://www.abcam.com/gshgssg-ratio-detection-assay-kit-fluorometric-green-ab138881.html">http://www.abcam.com/gshgssg-ratio-detection-assay-kit-fluorometric-green-ab138881.html</a>).   </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"> No </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px"> Thiobarbituric acid reactive substances (TBARS)  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> (Griendling, K. K., et al., 2016) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px"> Oxidative damage to lipids can be measured by assaying for lipid peroxidation with TBARS using a commercially available kit.   </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"> No </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px"> Protein oxidation (carbonylation) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> (Azimzadeh et al., 2017; Azimzadeh etal., 2015; Ping et al., 2020) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px"> Can be determined with enzyme-linked immunosorbent assay (ELISA) or a commercial assay kit. Protein oxidation can indicate the level of oxidative stress. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"> No </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px">Seahorse XFp Analyzer   </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px">Leung et al. 2018   </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px">The Seahorse XFp Analyzer provides information on mitochondrial function, oxidative stress, and metabolic dysfunction of viable cells by measuring respiration (oxygen consumption rate; OCR) and extracellular pH (extracellular acidification rate; ECAR).   </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px">No </td> </tr> </tbody> </table> Molecular Biology: Nrf2. Nrf2’s transcriptional activity is controlled post-translationally by oxidation of Keap1. Assays for Nrf2 activity include:  <table cellspacing="0" class="Table" style="border-collapse:collapse; width:623px"> <tbody> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:154px"> Method of Measurement  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:139px"> References  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:256px"> Description  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:75px"> OECD-Approved Assay </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:154px"> Immunohistochemistry  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:139px"> (Amsen, D., de Visser, K. E., and Town, T., 2009) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:256px"> Immunohistochemistry for increases in Nrf2 protein levels and translocation into the nucleus   </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:75px"> No </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:154px"> Quantitative polymerase chain reaction (qPCR)  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:139px"> (Forlenza et al., 2012) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:256px"> qPCR of Nrf2 target genes (e.g., Nqo1, Hmox-1, Gcl, Gst, Prx, TrxR, Srxn), or by commercially available pathway-based qPCR array (e.g., oxidative stress array from SABiosciences)  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:75px"> No </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:46px; vertical-align:top; width:154px"> Whole transcriptome profiling via microarray or via RNA-seq followed by a pathway analysis </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:46px; vertical-align:top; width:139px"> (Jackson, A. F. et al., 2014) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:46px; vertical-align:top; width:256px"> Whole transcriptome profiling by microarray or RNA-seq followed by pathway analysis (in IPA, DAVID, metacore, etc.) for enrichment of the Nrf2 oxidative stress response pathway </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:46px; vertical-align:top; width:75px"> No </td> </tr> </tbody> </table>

Taxonomic applicability: Occurrence of oxidative stress is not species specific.   Life stage applicability: Occurrence of oxidative stress is not life stage specific.  Sex applicability: Occurrence of oxidative stress is not sex specific.  Evidence for perturbation by prototypic stressor: There is evidence of the increase of oxidative stress following perturbation from a variety of stressors including exposure to ionizing radiation and altered gravity (Bai et al., 2020; Ungvari et al., 2013; Zhang et al., 2009).

High Mixed

High

All life stages

High High

Ahmad, S. et al. (2021), “60Co-γ Radiation Alters Developmental Stages of Zeugodacus cucurbitae (Diptera: Tephritidae) Through Apoptosis Pathways Gene Expression”, Journal Insect Science, Vol. 21/5, Oxford University Press, Oxford, <a href="https://doi.org/10.1093/jisesa/ieab080" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1093/jisesa/ieab080</a> Antelmann, H. and J. D. Helmann (2011), “Thiol-based redox switches and gene regulation.”, Antioxidants & Redox Signaling, Vol. 14/6, Mary Ann Leibert Inc., Larchmont, <a href="https://doi.org/10.1089/ars.2010.3400" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1089/ars.2010.3400</a> Amsen, D., de Visser, K. E., and Town, T. (2009), “Approaches to determine expression of inflammatory cytokines”, in Inflammation and Cancer, Humana Press, Totowa, <a href="https://doi.org/10.1007/978-1-59745-447-6_5" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1007/978-1-59745-447-6_5</a>  Azimzadeh, O. et al. (2015), “Integrative Proteomics and Targeted Transcriptomics Analyses in Cardiac Endothelial Cells Unravel Mechanisms of Long-Term Radiation-Induced Vascular Dysfunction”, Journal of Proteome Research, Vol. 14/2, American Chemical Society, Washington, <a href="https://doi.org/10.1021/pr501141b" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1021/pr501141b</a> Azimzadeh, O. et al. (2017), “Proteome analysis of irradiated endothelial cells reveals persistent alteration in protein degradation and the RhoGDI and NO signalling pathways”, International Journal of Radiation Biology, Vol. 93/9, Informa, London, <a href="https://doi.org/10.1080/09553002.2017.1339332" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1080/09553002.2017.1339332</a> Azzam, E. I. et al. (2012), “Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury”, Cancer Letters, Vol. 327/1-2, Elsevier, Ireland, https://doi.org/10.1016/j.canlet.2011.12.012  Bai, J. et al. (2020), “Irradiation-induced senescence of bone marrow mesenchymal stem cells aggravates osteogenic differentiation dysfunction via paracrine signaling”, American Journal of Physiology - Cell Physiology, Vol. 318/5, American Physiological Society, Rockville, <a href="https://doi.org/10.1152/ajpcell.00520.2019." style="color:#0563c1; text-decoration:underline">https://doi.org/10.1152/ajpcell.00520.2019.</a> Balasubramanian, D (2000), “Ultraviolet radiation and cataract”, Journal of ocular pharmacology and therapeutics, Vol. 16/3, Mary Ann Liebert Inc., Larchmont, <a href="https://doi.org/10.1089/jop.2000.16.285.%22%20/t%20%22_blank" rel="noreferrer noopener" target="_blank">https://doi.org/10.1089/jop.2000.16.285.</a>  Biesemann, N. et al., (2018), “High Throughput Screening of Mitochondrial Bioenergetics in Human Differentiated Myotubes Identifies Novel Enhancers of Muscle Performance in Aged Mice”, Scientific Reports, Vol. 8/1, Nature Portfolio, London, <a href="https://doi.org/10.1038/s41598-018-27614-8" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1038/s41598-018-27614-8</a>.  Elgazzar, A. and N. Kazem. (2015), “Chapter 23: Biological effects of ionizing radiation” in The Pathophysiologic Basis of Nuclear Medicine, Springer, New York, pp. 540-548 Fletcher, A. E (2010), “Free radicals, antioxidants and eye diseases: evidence from epidemiological studies on cataract and age-related macular degeneration”, Ophthalmic Research, Vol. 44, Karger International, Basel, <a href="https://doi.org/10.1159/000316476.%22%20/t%20%22_blank" rel="noreferrer noopener" target="_blank">https://doi.org/10.1159/000316476.</a>   Forlenza, M. et al. (2012), “The use of real-time quantitative PCR for the analysis of cytokine mRNA levels” in Cytokine Protocols, Springer, New York, <a href="https://doi.org/10.1007/978-1-61779-439-1_2" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1007/978-1-61779-439-1_2</a>  Forrester, S.J. et al. (2018), “Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology”, Physiological Reviews, Vol. 98/3, American Physiological Society, Rockville, <a href="https://doi.org/10.1152/physrev.00038.201" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1152/physrev.00038.201</a> Foyer, C. H., A. V. Ruban, and G. Noctor (2017), “Viewing oxidative stress through the lens of oxidative signalling rather than damage”, Biochemical Journal, Vol. 474/6, Portland Press, England, https://doi.org/10.1042/BCJ20160814  Ganea, E. and J. J. Harding (2006), “Glutathione-related enzymes and the eye”, Current eye research, Vol. 31/1, Informa, London, <a href="https://doi.org/10.1080/02713680500477347.%22%20/t%20%22_blank" rel="noreferrer noopener" target="_blank">https://doi.org/10.1080/02713680500477347.</a>  Griendling, K. K. et al. (2016), “Measurement of reactive oxygen species, reactive nitrogen species, and redox-dependent signaling in the cardiovascular system: a scientific statement from the American Heart Association”, Circulation research, Vol. 119/5, Lippincott Williams & Wilkins, Philadelphia, <a href="https://doi.org/10.1161/RES.0000000000000110" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1161/RES.0000000000000110</a> Guo, C. et al. (2013), “Oxidative stress, mitochondrial damage and neurodegenerative diseases”, Neural regeneration research, Vol. 8/21, Publishing House of Neural Regeneration Research, China, <a href="https://doi.org/10.3969/j.issn.1673-5374.2013.21.009" style="color:#0563c1; text-decoration:underline">https://doi.org/10.3969/j.issn.1673-5374.2013.21.009</a> Hargreaves, M., and L. L. Spriet (2020), “Skeletal muscle energy metabolism during exercise.”, Nature Metabolism, Vol. 2, Nature Portfolio, London, <a href="https://doi.org/10.1038/s42255-020-0251-4" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1038/s42255-020-0251-4</a> Hladik, D. and S. Tapio (2016), “Effects of ionizing radiation on the mammalian brain”, Mutation Research/Reviews in Mutation Research, Vol. 770, Elsevier, Amsterdam, <a href="https://doi.org/10.1016/j.mrrev.2016.08.003" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1016/j.mrrev.2016.08.003</a> Itoh, K., J. Mimura and M. Yamamoto (2010), “Discovery of the negative regulator of Nrf2, Keap1: a historical overview”, Antioxidants & Redox Signaling, Vol. 13/11, Mary Ann Leibert Inc., Larchmont, <a href="https://doi.org/10.1089/ars.2010.3222" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1089/ars.2010.3222</a> Jackson, A.F. et al. (2014), “Case study on the utility of hepatic global gene expression profiling in the risk assessment of the carcinogen furan.”, Toxicology and Applied Pharmacology, Vol. 274/11, Elsevier, Amsterdam, <a href="https://doi.org/10.1016/j.taap.2013.10.019" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1016/j.taap.2013.10.019</a> Jacobsen, N.R. et al. (2008), “Genotoxicity, cytotoxicity, and reactive oxygen species induced by single-walled carbon nanotubes and C60 fullerenes in the FE1-MutaTM Mouse lung epithelial cells”, Environmental and Molecular Mutagenesis, Vol. 49/6, John Wiley & Sons, Inc., Hoboken, <a href="https://doi.org/10.1002/em.20406" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1002/em.20406</a> Karimi, N. et al. (2017), “Radioprotective effect of hesperidin on reducing oxidative stress in the lens tissue of rats”, International Journal of Pharmaceutical Investigation, Vol. 7/3, Phcog Net, Bengaluru, <a href="https://doi.org/10.4103/jphi.JPHI_60_17.%E2%80%AF" rel="noreferrer noopener" target="_blank">https://doi.org/10.4103/jphi.JPHI_60_17.</a> Leung, D.T.H., and Chu, S. (2018), “Measurement of Oxidative Stress: Mitochondrial Function Using the Seahorse System” In: Murthi, P., Vaillancourt, C. (eds) Preeclampsia. Methods in Molecular Biology, vol 1710. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7498-6_22  Lu, C., G. Song, and J. Lin (2006), “Reactive oxygen species and their chemiluminescence-detection methods”, TrAC Trends in Analytical Chemistry, Vol. 25/10, Elsevier, Amsterdam, <a href="https://doi.org/10.1016/j.trac.2006.07.007" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1016/j.trac.2006.07.007</a> Nguyen Dinh Cat, A. et al. (2013), “Angiotensin II, NADPH oxidase, and redox signaling in the vasculature”, Antioxidants & redox signaling, Vol. 19/10, Mary Ann Liebert, Larchmont, <a href="https://doi.org/10.1089/ars.2012.4641" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1089/ars.2012.4641</a> Ping, Z. et al. (2020), “Oxidative Stress in Radiation-Induced Cardiotoxicity”, Oxidative Medicine and Cellular Longevity, Vol. 2020, Hindawi, <a href="https://doi.org/10.1155/2020/3579143" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1155/2020/3579143</a> Pizzino, G. et al. (2017) “Oxidative Stress: Harms and Benefits for Human Health.” Oxidative medicine and cellular longevity, Vol. 2017: 8416763, Hindawi,  https://doi.org/10.1155/2017/8416763    Powers, S.K. and M.J. Jackson. (2008), “Exercise-Induced Oxidative Stress: Cellular Mechanisms and Impact on Muscle Force Production”, Physiological Reviews, Vol. 88/4, American Physiological Society, Rockville, <a href="https://doi.org/10.1152/physrev.00031.2007" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1152/physrev.00031.2007</a> Raimondi, V., F. Ciccarese and V. Ciminale. (2020), “Oncogenic pathways and the electron transport chain: a dangeROS liason”, British Journal of Cancer, Vol. 122/2, Nature Portfolio, London, <a href="https://doi.org/10.1038/s41416-019-0651-y" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1038/s41416-019-0651-y</a> Seen, S. and L. Tong. (2018), “Dry eye disease and oxidative stress”, Acta Ophthalmologica, Vol. 96/4, John Wiley & Sons, Inc., Hoboken, <a href="https://doi.org/10.1111/aos.13526" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1111/aos.13526</a> Sharifi-Rad, M. et al. (2020), “Lifestyle, Oxidative Stress, and Antioxidants: Back and Forth in the Pathophysiology of Chronic Diseases.” Frontiers in physiology Vol. 11:694,  https://doi.org/10.3389/fphys.2020.00694    Snezhkina, A. V. et al. (2019), “ROS Generation and Antioxidant Defense Systems in Normal and Malignant Cells.” Oxidative medicine and cellular longevity Vol. 2019: 6175804, https://doi.org/10.1155/2019/6175804    Ungvari, Z. et al. (2013), “Ionizing Radiation Promotes the Acquisition of a Senescence-Associated Secretory Phenotype and Impairs Angiogenic Capacity in Cerebromicrovascular Endothelial Cells: Role of Increased DNA Damage and Decreased DNA Repair Capacity in Microvascular Radiosensitivity”, The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, Vol. 68/12, Oxford University Press, Oxford, <a href="https://doi.org/10.1093/gerona/glt057." style="color:#0563c1; text-decoration:underline">https://doi.org/10.1093/gerona/glt057.</a>   Vargas-Mendoza, N. et al. (2021), “Oxidative Stress, Mitochondrial Function and Adaptation to Exercise: New Perspectives in Nutrition”, Life, Vol. 11/11, Multidisciplinary Digital Publishing Institute, Basel, <a href="https://doi.org/10.3390/life11111269" style="color:#0563c1; text-decoration:underline">https://doi.org/10.3390/life11111269</a> Wang, H. et al. (2019), “Radiation-induced heart disease: a review of classification, mechanism and prevention”, International Journal of Biological Sciences, Vol. 15/10, Ivyspring International Publisher, Sydney, <a href="https://doi.org/10.7150/ijbs.35460" style="color:#0563c1; text-decoration:underline">https://doi.org/10.7150/ijbs.35460</a> Zhang, R. et al. (2009), “Blockade of AT1 receptor partially restores vasoreactivity, NOS expression, and superoxide levels in cerebral and carotid arteries of hindlimb unweighting rats”, Journal of applied physiology, Vol. 106/1, American Physiological Society, Rockville, <a href="https://doi.org/10.1152/japplphysiol.01278.2007" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1152/japplphysiol.01278.2007</a>. Zhao, R. Z. et al. (2019), “Mitochondrial electron transport chain, ROS generation and uncoupling”, International journal of molecular medicine, Vol. 44/1, Spandidos Publishing Ltd., Athens, <a href="https://doi.org/10.3892/ijmm.2019.4188" style="color:#0563c1; text-decoration:underline">https://doi.org/10.3892/ijmm.2019.4188</a> AOPWiki 2017-05-30T13:58:17

2024-03-08T12:28:08

Acrolein accumulation

Cellular

Acrolein is an unsaturated aldehyde created through both endogenous and exogenous means. Acrolein is a metabolite in lipid peroxidation, can be synthesized for commercial use, and can also become a metabolite in some substrate detoxification<cite> (Uchida et.al., 1998, Ibrahim, et al., 2023)</cite>. Acrolein accumulation has been known to lead to oxidative stress through the generation of reactive oxygen species as well as form acrolein -protein or acrolein-DNA adducts thus leading to cell damage, apoptosis, mitochondrial disfunction or cancer (<cite>Hong et.al, 2020, Ibrahim, et al., 2023, Burcham et al., 2006, Luo et al., 2007)</cite>. On an organ level, acrolein-induced oxidative stress is associated with severe toxicity in the renal system <cite>(Moghe et al., 2015)</cite>.  Protein adducts: Acrolein is a strong electrophile (electron-loving) and is high reactivity with cellular nucleophiles such as proteins, DNA and RNA. As such, acrolein readily targets the sulfhydryl group of cysteine, the imidazole group of histidine, and the amino group of lysine which results in the acrolein-protein connections via these amino acids. The accumulation of acrolein protein adducts can result in improper protein folding and also lead to ER stress (<cite>Moghe et al., 2015</cite>). One major data gap is that the mechanisms by which acrolein induces ER stress remain unknown but may be a combination of oxidative stress, protein, or DNA adduct formation <cite>(Haberzettl et al., 2008).</cite> DNA adducts:  Acrolein can cause DNA damage through many pathways such as (Reactive oxygen species) ROS production and adduct formation which have both been linked to mutations and carcinogenesis. Acrolein being very electrophilic can create cross-links of double-stranded DNA as well as DNA-protein cross-links. Acrolein readily reacts with deoxyguanosine (dG) producing two exocyclic DNA adducts, α- and γ-hydroxy-1, N2-propano-2′-deoxyguanosine (α-HOPdG and γ-HOPdG), which have been linked to mutations <cite>(Tang et al., 2011)</cite>. There have also been reports of acrolein adducts with  2′-deoxyadenosine, 2-deoxycytidine DNA bases, and thymidine. This adduct formation has been studied both in vitro and in vivo in several animal tissues, human tissues, and cells (T<cite>ang et al., 2011; Voulgaridou et al., 2011</cite>). Oxidative stress: Many processes such as bioactivation and mitochondrial cellular respiration produce ROS like superoxide which can damage lipids, proteins, carbohydrates, and nucleic acids. This damage occurs when highly Some endogenous and exogenous remedies to reactive oxygen species are antioxidant compounds like vitamin C and antioxidant enzymes like superoxide dismutase (SOD). The imbalance of ROS can overwhelm these defense mechanisms, which in turn results in a phenomenon called oxidative stress (Moghe et al., 2015). In vivo and in vitro studies confirm that acrolein can itself cause oxidative damage, leading DNA and mitochondrial damage and can exacerbate apoptosis. Acrolein exposure has been seen to significantly increase oxidant levels by decreasing the antioxidant glutathione, anti-oxidant enzymes (SOD and GSH-peroxidase), and total and nuclear levels of the antioxidant regulator-Nrf2 (<cite>Moghe et al., 201</cite>5). Inflammation: Acrolein has been seen to not only be a product of lipid peroxidation but also an initiator for some inflammatory pathways. For instance, some studies have shown acrolein can activate NF-κB and induce proinflammatory mediators in rat lung epithelial cells from only acute acrolein exposure. Acrolein exposure was seen to induce the NF-κB dependent marker of inflammation, COX-2 via calcium release and subsequent proteolytic degradation of IκBα. <cite>(Sarkar and Hayes, 2007)</cite>. In addition. inflammatory IL-8 upregulation is associated with many inflammatory disorders, and IL-8 production due to acrolein exposure has been studied in vitro in multiple cell types, including multiple human cells (<cite>Moghe et al., 2015).</cite>

•    Mass Spectroscopy: Gas and liquid chromatography tandem mass spectroscopy (Lc-MS and GC-MS) have been used to separate and detect acrolein adducts and other lipid peroxidation markers in humans. Samples containing acrolein are first cleaned by extractions (either solid phase or solvent extractions depending on the sample type) and purified further via LC or GC, following this the mass to charge ratio of acrolein can be viewed via mass spectroscopy. One easy and notable way is electronspray ionization mass spectroscopy<cite> (Uchida et.al., 1998)</cite>. With those detection methods in mind, there are many ways to sample acrolein-adducts such as blood, saliva, tissue, and urine samples (<cite>Hirose et al., 2015, Hikisz & Jacenik 2023, Bispo et al., 2016). </cite> •    Spectroscopy: The characteristic absorbance of acrolein-adduct formation has also been studied and used as a preliminary qualitative screen for further quantitative testing in some studies. The fundamentals of this method has been studied through both testing in human samples and simulation of the protein adduct formation in vivo. The simulation includes reacting a sample containing acrolein with Nα-acetyllysine or Nα-acetylhistidine  to create protein-acrolein adducts, purifying the sample with liquid chromatography, then measuring the absorbance at the respective wavelength depedning on the adduct of interest <cite>(Uchida et.al., 1998).</cite> •    Immunoblotting: Acrolein-protein adducts can be separated and measured with techniques such as western blotting or enzyme linked immunosorbent assays, also know as ELISA's<cite> (Chen et al., 2016)</cite>. These techniques both include exposing proteins to a primary anti-body specific to the acrolein adduct of interest, followed by washing and the addition of a secondary antibody. The outcome of these exposures and therefore presence of acrolein adducts can be read through chemiluminescent reactions. For ELISA this is done through an ELISA microplate reader and for western blotting through membrane imagine apparatus<cite> (Uchida et.al., 1998). </cite> •    Histology:  When a tissue sample is obtained another method used to measure or detect acrolein presence via adducts is histology. In this method a sample of cross sectioned tissue is obtained, fixed, and stained with polyclonal antibodies specific for the acrolein adduct of interest. Following this, the tissue can be examined via light microscopy for the appearance of acrolein adducts and quantified using imaging software. This technique can also be applied to certain cells such as most hepatocytes <cite>(Chen et al., 2016).</cite>

<ul> <li>D: Taxonomic applicability:  Most data was generated from human studies, rat, or mice studies <cite>(Uchida et. al., 1998, Wang et al., 2012, </cite><cite>Chen et al., 2016</cite><cite>).</cite></li> <li>E: Life stages: The domain of applicability for life stages is all life stages. </li> <li>F: Sex applicability: The domain of applicability for sex is both males and females.</li> </ul>

High Mixed

High

Adults

High High High Bispo VS, de Arruda Campos IP, Di Mascio P, Medeiros MH. (2016) Structural Elucidation of a Carnosine-Acrolein Adduct and its Quantification in Human Urine Samples. Sci Rep. 19;6:19348.  Burcham PC, Pyke SM. Hydralazine inhibits rapid acrolein-induced protein oligomerization: role of aldehyde scavenging and adduct trapping in cross-link blocking and cytoprotection. Mol Pharmacol. 2006;69:1056–1065. Chen WY, Zhang J, Ghare S, Barve S, McClain C, Joshi-Barve S. (2016) Acrolein Is a Pathogenic Mediator of Alcoholic Liver Disease and the Scavenger Hydralazine Is Protective in Mice. Cell Mol Gastroenterol Hepatol. 27;2(5):685-700. Haberzettl P, Vladykovskaya E, Srivastava S, Bhatnagar A. Role of endoplasmic reticulum stress in acrolein-induced endothelial activation. Toxicol Appl Pharmacol. 2009 Jan 1;234(1):14-24 Hikisz, P.; Jacenik, D. (2023) Diet as a Source of Acrolein: Molecular Basis of Aldehyde Biological Activity in Diabetes and Digestive System Diseases. Int. J. Mol. Sci. , 24, 6579. Hirose T, Saiki R, Uemura T, Suzuki T, Dohmae N, Ito S, Takahashi H, Ishii I, Toida T, Kashiwagi K, Igarashi K. (2015) Increase in acrolein-conjugated immunoglobulins in saliva from patients with primary Sjögren's syndrome. Clin Chim Acta. 450:184-9.  Ibrahim, K.M., Darwish, S.F., Mantawy, E.M. et al. Molecular mechanisms underlying cyclophosphamide-induced cognitive impairment and strategies for neuroprotection in preclinical models. Mol Cell Biochem (2023). Jian-Hua Hong, Priscilla Ann Hweek Lee, Yu-Chuan Lu, Cheng-Yu Huang, Chung-Hsin Chen, Chih-Hung Chiang, Po-Ming Chow, Fu-Shan Jaw, Chung-Chieh Wang, Chao-Yuan Huang, Tse-Wen Wang, Jin-Hui Liu, Hsiang-Tsui Wang, (2020) Acrolein contributes to urothelial carcinomas in patients with chronic kidney disease, Urologic Oncology: Seminars and Original Investigations, 38 (5) 465-475, Koji Uchida, Masamichi Kanematsu, Yasujiro Morimitsu, Toshihiko Osawa, Noriko Noguchi, Etsuo Niki, (1998) Acrolein Is a Product of Lipid Peroxidation Reaction: FORMATION OF FREE ACROLEIN AND ITS CONJUGATE WITH LYSINE RESIDUES IN OXIDIZED LOW DENSITY LIPOPROTEINS*, Journal of Biological Chemistry. Luo J, Hill BG, Gu Y, Cai J, Srivastava S, Bhatnagar A, Prabhu SD. (2007 )Mechanisms of acrolein-induced myocardial dysfunction: implications for environmental and endogenous aldehyde exposure. Am J Physiol Heart Circ Physiol. Moghe A, Ghare S, Lamoreau B, Mohammad M, Barve S, McClain C, Joshi-Barve S. (2015) Molecular mechanisms of acrolein toxicity: relevance to human disease. Toxicol Sci. ;143(2):242-55. Sarkar P., Hayes B. E. (2007). Induction of COX-2 by acrolein in rat lung epithelial cells. Mol. Cell. Biochem. 301, 191–199. Tang M. S., Wang H. T., Hu Y., Chen W. S., Akao M., Feng Z., Hu W. (2011). Acrolein induced DNA damage, mutagenicity and effect on DNA repair. Mol. Nutr. Food Res. 55, 1291–1300 Voulgaridou G. P., Anestopoulos I., Franco R., Panayiotidis M. I., Pappa A. (2011). DNA damage induced by endogenous aldehydes: current state of knowledge. Mutat. Res. 711, 13–27 Wang SP, Chen YH, Li H. (2012) Association between the levels of polyunsaturated fatty acids and blood lipids in healthy individuals. Exp Ther Med. 4(6):1107-1111.       AOPWiki 2024-06-03T03:00:22

2024-06-18T22:16:33

Chronic kidney disease

Organ

Chronic kidney disease is the presence of kidney damage or an overall lowered estimated glomerular filtration rate of less than 60 ml/min that has persisted for 3 months or more, regardless of the cause. This disease is progressive and can be characterized as the loss of kidney function through kidney damage, ultimately resulting in dialysis treatment or a kidney transplantation. Kidney damage can be seen when abnormalities either suggested by imaging studies through a renal biopsy, abnormalities in urinary sediment, or increased urinary albumin excretion rates are observed. The most common risk for kidney disease are genetic predisposition or chronic kidney injury through inflammation, xenobiotic exposure, or persistent infection. For example, sickle cell trait and the presence of 2 APOL1 risk alleles may double the chance of chronic kidney disease. Without treatment, this condition is almost always lethal <cite>(Vaidya & Aeddula et al., 2022, Chen et al., 2019).</cite>

<ul> <li> Chronic kidney disease can be directly measured by calculating the glomerular filtration rate. This can be achieved by urine sample analysis through the clearance of administered chemicals such as iohexol or iothalamate <cite>(Brown & O’Reilly, 1991)</cite>. More recently, filtration markers current in the blood have been used such as creatinine ratio, a metabolite of creatine. To gauge the level of kidney damage and therefore the stage of kidney disease, in addition to filtration rate, urine albumin-to-creatine ratio can be calculated again from urine sample analysis. In addition, Cystatin C, which is a kidney injury molecule, and neutrophil gelatinase-associated lipocalin sera levels are more sensitive than serum creatinine in the detection of acute kidney injury<cite> (Al-Naimi et al., 2019)</cite>. Kidney imagining by ultrasound can also be done to assess kidney disease stages through morphology and obstruction assessment (<cite>Chen et al., 2019)</cite>.     </li> <li>  In human’s chronic kidney disease can be detected through routine screening with serum chemistry profile and urine studies. Many early stages of kidney diseases are asymptomatic however some later stage symptoms such as foamy urine ( also called gross hematuria which is a sign of albuminuria), the need to urinate in the middle of the night (nocturia), side pain, or decreased urine output are strong indications of chronic kidney disease. If the disease is advanced, symptoms may also include fatigue, loss of appetite, vomiting, unintentional weight loss, pruritus, dyspnea, changes in mental state. or peripheral edema <cite>(Chen et al., 2019). </cite></li> </ul>

<ul> <li>D: Taxonomic applicability:  Chronic kidney disease can occur in many vertebrate species including cats, dogs, and humans (<cite>Bartges et al., 2012, Chen et al., 2019, Brown & O’Reilly, 1991</cite>).</li> <li>E: Life stages: The domain of applicability for life stages is all life stages. </li> <li>F: Sex applicability: The domain of applicability for sex is both males and females.</li> </ul>

UBERON:0002113

UBERON kidney

High Mixed

High

Adult

High High Al-Naimi, M. S., Rasheed, H. A., Hussien, N. R., Al-Kuraishy, H. M., & Al-Gareeb, A. I. (2019). Nephrotoxicity: Role and significance of renal biomarkers in the early detection of acute renal injury. Journal of advanced pharmaceutical technology & research, 10(3), 95–99. Bartges JW. Chronic kidney disease in dogs and cats. (2012) Vet Clin North Am Small Anim Pract. Jul;42(4):669-92, Brown SC, O’Reilly PH. (1991) Iohexol clearance for the determination of glomerular filtration rate in clinical practice: evidence for a new gold standard. J Urol. ;146(3):675–679. Chen, T. K., Knicely, D. H., & Grams, M. E. (2019). Chronic Kidney Disease Diagnosis and Management: A Review. JAMA, 322(13), 1294–1304 Gouvernement du Canada. (2024, June 15). Government of Canada. Drug and Health Products Portal. https://dhpp.hpfb-dgpsa.ca Hartung E. A. (2016). Biomarkers and surrogate endpoints in kidney disease. Pediatric nephrology (Berlin, Germany), 31(3), 381–391. Vaidya SR, Aeddula NR. (2022) Chronic Kidney Disease. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 202   AOPWiki 2019-02-18T09:58:11

2024-06-16T00:04:01

Increased, Lipid peroxidation

Increased, LPO

Molecular

Lipid peroxidation is the direct damage to lipids in the membrane of the cell or the membranes of the organelles inside the cells. Ultimately the membranes will break due to the build-up damage in the lipids. This is mainly caused by oxidants which attack lipids specifically, since these contain carbon-carbon double bonds. During lipid peroxidation several lipid radicals are formed in a chain reaction. These reactions can interfere and stimulate each other. Antioxidants, such as vitamin E, can react with lipid peroxy radicals to prevent further damage in the cell (Cooley et al. 2000).

The main product of lipid peroxidation, malondialdehyde and 4-hydroxyalkenals, is used to measure the degree of this process. This is measured by photocolorimetric assays, quantification of fatty acids by gaseous liquid chromatography (GLC) or high performance (HPLC) (L. Li et al. 2019; Jin et al. 2010a) or through commercial kits purchased from specialized companies.

ROS is a normal constituent found in all organisms, therefore, all organisms containing lipid membranes may be affected by lipid peroxidation.  Structure: Regardless of sex or life stage, when exposed to free radicals, there is potential for lipid peroxidation as a auxiliary response where there are lipid membranes.

High Unspecific

High

All life stages

Moderate High

Cooley HM, Evans RE, Klaverkamp JF. 2000. Toxicology of dietary uranium in lake whitefish (Coregonus clupeaformis). Aquatic Toxicology. 48(4):495–515. https://doi.org/10.1016/S0166-445X(99)00057-0 Jin, Yuanxiang, Xiangxiang Zhang, Linjun Shu, Lifang Chen, Liwei Sun, Haifeng Qian, Weiping Liu, and Zhengwei Fu. 2010a. “Oxidative Stress Response and Gene Expression with Atrazine Exposure in Adult Female Zebrafish (Danio Rerio).” Chemosphere 78 (7): 846–52. Li, Luxiao, Shanshan Zhong, Xia Shen, Qiujing Li, Wenxin Xu, Yongzhen Tao, and Huiyong Yin. 2019. “Recent Development on Liquid Chromatography-Mass Spectrometry Analysis of Oxidized Lipids.” Free Radical Biology & Medicine 144 (November): 16–34. AOPWiki 2017-06-29T08:04:27

2023-07-27T10:25:14

<upstream-id>7d8d5e2a-5a2a-465e-a8f7-f337f72668ed</upstream-id> <downstream-id>e71b4079-6c01-4b8e-8cf6-661383e0544d</downstream-id>

AOPWiki 2024-06-04T21:32:28

2024-06-04T21:32:28

<upstream-id>e71b4079-6c01-4b8e-8cf6-661383e0544d</upstream-id> <downstream-id>a90c4a88-2995-4e04-86ca-f3ed9f870a92</downstream-id>

AOPWiki 2024-06-04T21:34:10

2024-06-04T21:34:10

<upstream-id>e71b4079-6c01-4b8e-8cf6-661383e0544d</upstream-id> <downstream-id>9a6b229b-0116-46f5-81ce-d47cdbd8a67b</downstream-id> The imbalance of reactive oxygen species to antioxidants, also known as oxidative stress, can result in lipid peroxidation. It has been well studied and established that radicals such as superoxide’s can interact with nucleophilic centers in the body like lipids in membrane bylayers. These lipids are composed of polyunsaturated fasts (PUFAs) like arachidonic acid which can become oxidized and lead to a chain reaction of oxidized lipids. More specifically, oxidation of PUFAS leads to the formation of another radical, a lipoperoxyl (LOO•), which, in turn, reacts with other lipids to yield not only another lipid radical but also a lipid hydroperoxide (LOOH). Although lipid hydroperoxides are unstable they offer some local adverse effects and can also create new radicals that decompose to secondary products with longer half-lives. These breakdown products include aldehydes such as acrolein and hexanal which can diffuse and react outside of its site of formation<cite> (Barrera et al., 2012)</cite>.  Antioxidants, such as vitamins or antioxidant enzymes, can react with lipid peroxy radicals to prevent further damage in the cell <cite>(Cooley et al., 2000)</cite>. In addition to this, antioxidants and antioxidant enzymes can also interact with reactive oxygen species to prevent ROS damage.

N/A

The biological plausibility for this key event relationship is strong: The relationship and mechanism between oxidative stress leading to lipid peroxidation is very well established and studied.

The empirical evidence for this key event relationship is Strong. There are many studies linking oxidative stress to lipid peroxidation within both in vivo and in vitro research articles and most articles describe the mechanisms behind this KER. Dose concordance: An additional study that demonstrates great dose concordance in vivo is the administration of acrolein at concentration of 0-100 uM to human vascular endothelial cells. It was shown that exogenous acrolein can initiate oxidative stress and as a down stream result, lipid peroxidation through the creation of reactive oxygen species. A recent study in 2022 measured reactive oxygen species through two ROS specific dyes (MitoSox and DCH-DA) which revealed a significant increase in ROS at 50 uM of acrolein when compared to the control. In addition, the concentration of acrolein needed to induce a significant change in MDA measured cells was 100 uM thus proving that a lower dose was required to induce oxidative stress in human vascular endothelial cells than with lipid peroxidation via MDA measurement <cite>(Zhou et al, 2022).</cite> One new dose concordance example follows the administration the ROS generating pharmaceutical- cyclophosphamide at concentrations of 0, 10, and 20 ug/ml to testicular Leydig cells. In this study it was seen that as the concentration of cyclophosphamide increased, the concentration of reactive oxygen species measured (via a ROS assay kit) very significantly increased at 10ug/ml. In addition, the concentration of MDA (measured via an MDA assay kit) followed a similar trend however only slightly significantly increased after 10 ug/ml of cyclophosphamide. This study showed that oxidative stress via reactive oxygen species required the same dose of stressor to illicit change in lipid peroxidation <cite>(Liao et al, 2024). </cite> Another example of dose concordance with this KER is paraquat and hydrogen peroxide application to Vibrio cholerae <cite>(Abrashev et al., 2011)</cite>.  This study also demonstrated that the dose required for oxidative stress was less than/ equal to that needed to induce lipid peroxidation but through indirect markers. Cells were exposed to paraquat and hydrogen peroxide separately for one hour at concentrations of  0, 0.1, 0.3, 0.5, 1.0, 2.0, 3.0 mM. This resulted in increasing amounts of reactive oxygen species (specifically superoxide radicals and hydrogen peroxide) at 0.3 mM and higher. Similarly, lipid peroxidation and overall oxidative damage through protein carbonylation was measured at similar doses of 0, 0.1, 0.5, and 1 mM and showed the most change at 0.5 mM of paraquat <cite>(Abrashev et al., 2011, Rodríguez-García et al., 2020).</cite>  One final example of dose concordance is an in vitro study which exposed purified rat liver microsomal lipids to paraquat (a well studied oxidative stress inducer) in the presences of a NADPH-cytochrome c reductase. The cytochrome enzyme was included to interact with paraquat and include radicals which could then be measured against Malondialdehyde (MDA) concentrations as a result of lipid peroxidation. It was seen that as the concentration of paraquat increased from 0-0.0001 M the concentration of MDA also increased from 0.37 nmole/min/ml to 1.21 nmole/min/ml <cite>(Bus et al, 1976)</cite>. To make this study a perfect dose concordance experiment, including the concentration of reduced paraquat radicals would further the explanation of oxidative stress leading to lipid peroxidation.   Temporal concordance: One example of temporal concordance regarding the relationship between oxidative stress and lipid peroxidation is the application of paraquat to mouse fibroblasts <cite>(Peter et al., 1991)</cite>. As the concentration of paraquat increased from 0-2.5 mM, and as a result radicals increased, the concentration of MDA also increased. MDA is a known metabolite of lipid peroxidation which was measured from 0-4 hours <cite>(Peter et al., 1991)</cite>. To make this a perfect temporal concordance experiment depiction, one would also need to include the measurement of an oxidative stress marker like reactive oxygen species production. This could be done by measuring superoxide radicals similar to the study done by Abrashev in 2011. This study with these modifications would be very fundamental in depicting oxidative stress preceding lipid peroxidation.  In addition, reactive oxygen species as a result of hyperglycemia in a study conducted in humans has been recommended to depict in vivo temporal concordance for future studies. Where an increase in glucose plasma levels overtime occurs before the occurrence of lipid peroxidation markers like MDA and 8-isoPGF2α <cite>(Ito et al., 2020)</cite> Incidence concordance: Much of the data found regarding incidence concordance was imperfect (just lacking population effects or 1/2 key event measurments) however one could expose a population of cells to an oxidative stress inducers like paraquat and measure the amount of lipid peroxidation and oxidative stress through ROS and oxidized lipid specific dyes with microscopy. Following this, one could measure the frequency of cells that show signs of oxidative stress (ex through ROS fluorescent dyes, which would show high fluorescence) and compare that to cells showing signs of lipid peroxidation (for instance a higher amount of membrane damage). A singular probe that can achieve this is Lipid Peroxidation Probe -BDP and has been used by multiple studies for similar experiments <cite>(Ma et al., 2023, Yang et al., 2023)</cite>. Hypothetically one should see a higher amount of cells conveying oxidative stress than cells conveying lipid peroxidation for incidence concordance to be true.

The mechanism for this KER is very well understood and there is a high degree of concordance between many species, so far no large uncertainties or inconsistencies have been found.

<div>N/A <table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>MF Specification</th> <th>Effect(s) on the KER</th> <th>Reference(s)</th> </tr> </thead> <tbody> <tr> <td> </td> <td> </td> <td> </td> <td> </td> </tr> </tbody> </table> </div>

Due to the fact that oxidative stress can originate from many factors, there are a vast amount of species that experience this phenomenon, and that there are multiple markers of lipid peroxidation, there is no set quantitative amount of oxidative stress that needs to occur before lipid peroxidation can be seen. However, it is widely accepted that continuous oxidative stress can result in lipid peroxidation.

N/A

High Mixed

High

All life stages

High

<ul> <li>Taxonomic applicability:  Most data was generated from human studies, bacteria, rat, or mice studies however ROS can affect all organisms containing lipid membranes and thus may be affected by lipid peroxidation due to oxidative stress.</li> <li>Life stages: The domain of applicability for life stages is all life stages. </li> <li> Sex applicability: The domain of applicability for sex is both males and females.</li> <li>The biological plausibility for this key event relationship is strong.</li> <li>The empirical evidence for this key event relationship is Strong.  </li> </ul>

Abrashev R, Krumova E, Dishliska V, Eneva V, Engibarov S, Abrashev I & Angelova M, (2011) Differential Effect of Paraquat and Hydrogen Peroxide on the Oxidative Stress Response in Vibrio Cholerae Non O1 26/06, Biotechnology & Biotechnological Equipment, 25:sup1, 72-76, Barrera G. (2012). Oxidative stress and lipid peroxidation products in cancer progression and therapy. ISRN oncology, 2012, 137289. Bus J, Aust S, Gibson J. (1976). Paraquat Toxicity: Proposed Mechanism of Action Involving Lipid Peroxidation. Environmental health perspectives. 16. 139-46. Cooley HM, Evans RE, Klaverkamp JF. (2000). Toxicology of dietary uranium in lake whitefish (Coregonus clupeaformis). Aquatic Toxicology. 48(4):495–515.  Ito F, Sono Y, Ito T. (2019) Measurement and Clinical Significance of Lipid Peroxidation as a Biomarker of Oxidative Stress: Oxidative Stress in Diabetes, Atherosclerosis, and Chronic Inflammation. Antioxidants (Basel).  Mar 25;8(3):72. doi: 10.3390/antiox8030072. Liao S, Wei C, Wei G, Liang H, Peng F, Zhao L, Li Z, Liu C, Zhou Q, (2024) Cyclophosphamide activates ferroptosis-induced dysfunction of Leydig cells via SMAD2 pathway, Biology of Reproduction, (110) 5,1012-1024, Ma D, Liu J, Wang L, Zhi X, Luo L, Zhao J, Qin Y., (2023) GSK-3β-dependent Nrf2 antioxidant response modulates ferroptosis of lens epithelial cells in age-related cataract, Free Radical Biology and Medicine, 204,161-176, Peter B, Wartena M, Kampinga HH, Konings AW. (1991) Role of lipid peroxidation and DNA damage in paraquat toxicity and the interaction of paraquat with ionizing radiation. Biochem Pharmacol.  Feb 18;43(4):705-15. Rodríguez-García A, García-Vicente R, Morales ML, Ortiz-Ruiz A, Martínez-López J, Linares M. (2020) Protein Carbonylation and Lipid Peroxidation in Hematological Malignancies. Antioxidants (Basel). Dec 1;9(12):1212 Yang H, Zhang X, Ding Y, Xiong H, Xiang S, Wang Y, Li H, Liu Z, He J, Tao Y, et al (2023). Elabela: Negative Regulation of Ferroptosis in Trophoblasts via the Ferritinophagy Pathway Implicated in the Pathogenesis of Preeclampsia. Cells.; 12(1):99.  Zhou Y, Xu H, Cheng K, Chen F, Zhou Q, Wang M. (2022) Acrolein evokes inflammation and autophagy-dependent apoptosis through oxidative stress in vascular endothelial cells and its protection by 6-C-(E-2-fluorostyryl)naringenin, Journal of Functional Foods, 98, 1756-4646,  AOPWiki 2024-01-24T10:49:21

2024-06-20T20:55:33

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AOPWiki 2024-06-04T21:33:25

2024-06-04T21:33:25

<upstream-id>534712f2-cccc-48eb-971a-9927a7bed89e</upstream-id> <downstream-id>a90c4a88-2995-4e04-86ca-f3ed9f870a92</downstream-id>

AOPWiki 2024-06-04T21:33:36

2024-06-04T21:33:36

CYP450 upregulation leads to Chronic kidney disease

Arthur Author

Amanda Ameyaa-Sakyi

BY-SA

2.6

Cytochrome P450 (CYP450) enzymes are a class of mono-oxygenase's that metabolize and bioactivate multiple substrates. As such, CYP450 enzymes occasionally facilitate the creation of electrophilic metabolites such as superoxide radicals thus leading to oxidative damage. Some prototypical stressors and substrates of this AOP include small compounds like acrolein, cyclophosphamide, and Ifosfamide. The bioactivation and creation of reactive oxygen species by CYP450 and substrates interactions can lead to a phenomenon known as oxidative stress which is defined as the imbalance of reactive oxygen species to antioxidants. Oxidative stress imposes health risks to many taxa as it can lead to cellular damage in the form of lipid peroxidation and ultimately can lead to ailments such as chronic kidney disease in humans. In this adverse outcome pathway (AOP), one can find information leading to events and event relationships that may possibly connect prolonged upregulation of CYP450 (The molecular initiating event) to Chronic kidney disease (the adverse outcome). The key events that compose this AOP are oxidative stress (KE1), lipid peroxidation (KE2), and acrolein accumulation (KE3). Generally, most of these events can occur anywhere in the body where CYP450's are located however for this adverse outcome, CYP450's associated with the kidneys are of interest. The molecular initiating event (MIE) occurs when CYP450's interact with a substrate. The metabolism and subsequent bioactivation of the substrate promotes reactive oxygen species formation which then produces oxidative stress (KE1), these electrophilic reactive oxygen species attack nucleophilic centres in the cell such as lipids found in membrane lipid bilayers, resulting in lipid peroxidation (KE2). Following prolonged membrane injury via lipid peroxidation, the accumulation of a reactive cytotoxic lipid peroxidation metabolite known as acrolein can occur (KE3). Therefore, under chronic upregulation of CYP450 expression, excessive oxidative stress, increased lipid peroxidation and nephrotic injury via reactive acrolein accumulation, chronic kidney disease can occur (AO). Through the evaluation of biological plausibility, empirical support for the KERs, and quantitative understanding of this AOP, most events and their relationships are well supported by a large body of scientific literature and mechanistic understanding. Multiple taxa from rats to humans were explored in this AOP against CYP450 substrates like cyclophosphamide which is known to cause nephrotoxicity and chronic kidney disease. Further development of the quantitative aspects of this AOP can address research gaps regarding empirical links between acrolein accumulation and chronic kidney diseases.

Chronic kidney disease and its related endpoints are a large public health threat and as such exposure to known nephrotoxic drugs are regulated and newer nephrotoxins are surveilled by the government of Canada (https://dhpp.hpfb-dgpsa.ca). Interestingly, the number of clinical trials in nephrology lags behind many other fields. This can be due to the fact that clinical endpoints require progression and can take years to decades to be prevalent in patients. Standard and traditional biomarkers, such as serum creatinine may lack sensitivity and predictive value as it takes a lot of time to build up and be detected. One way to help to accelerate nephrology clinical trials can be by finding new biomarkers that can be detected quicker to serve as a new/ surrogate endpoint in clinical trials<cite> (Hartung, 2016). </cite>

adjacent

Not Specified

Not Specified adjacent

High

High adjacent

Not Specified

Not Specified adjacent

Not Specified

Not Specified non-adjacent

Not Specified

High Mixed

High

Adults

High

<table cellspacing="0" class="Table" style="border-collapse:collapse; border:none; margin-left:96px; width:542px"> <tbody> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:79px"> KER </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:281px"> Summary of Bio. Plausibility Evidence* </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:182px"> WOE call </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:79px"> KER 1  CYP450 upregulationà oxidative stress </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:281px"> It is well known that CYP450 upregulation in response to a stressor results in more bioactivation and/ or uncoupling of the enzyme which causes the release of reactive oxygen species in the cell leading to oxidative stress. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:182px"> High </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:79px"> KER 2 oxidative stress  à lipid peroxidation </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:281px"> Many empirical studies convey the dependent change of lipid peroxidation on oxidative stress following exposure to a wide range of ROS inducing stressors dose wise and time wise and is widely accepted. No contradictions or critical research gaps were noted with this KER. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:182px"> High </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:79px"> KER 3 lipid peroxidation à acrolein accumulation </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:281px"> It is well studied and accepted that a main reactive by product of lipid peroxidation is acrolein and the mechanisms linking these events is very well researched, understood, and defined. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:182px"> High </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:79px"> KER 4 acrolein accumulation  à chronic kidney disease </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:281px"> Acrolein accumulation leading to chronic kidney disease is plausible based on analogy to accepted biological relationships and mechanisms to tubular necrosis, however few studies have completely established a clear relationship regarding chronic kidney disease. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:182px"> Moderate </td> </tr> </tbody> </table>   <table cellspacing="0" class="Table" style="border-collapse:collapse; border:none; margin-left:96px; width:542px"> <tbody> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:79px"> KER </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:281px"> Summary of Empirical Evidence* </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:182px"> WOE call </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:79px"> KER 1  CYP450 upregulationà oxidative stress </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:281px"> There is a plethora of empirical evidence in vivo and in vitro across multiple species that demonstrates CYP450 upregulation increase oxidative stress, notably through reactive oxygen species generation. Many studies have outlined both the dose and temporal concordance of this key event relationship. No contradictions were noted with this KER. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:182px"> High </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:79px"> KER 2 oxidative stress  à lipid peroxidation </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:281px"> Many empirical studies convey the dependent change of lipid peroxidation on oxidative stress following exposure to a wide range of ROS inducing stressors dose wise and time wise and is widely accepted. No contradictions or critical research gaps were noted with this KER. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:182px"> High </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:79px"> KER 3 lipid peroxidation à acrolein accumulation </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:281px"> Multiple studies outline the mechanism creation of acrolein as an endogenous byproduct of lipid peroxidation and as an exogenous compound that can initiate this AOP's cascade. No contradictions were noted for this KER. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:182px"> High </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:79px"> KER 4 acrolein accumulation  à chronic kidney disease </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:281px"> limited studies report acrolein accumulation leading to chronic kidney disease in many taxa following exposure to a specific stressor. Many studies utilized quickly occurring or measurable endpoints such as tubular necrosis, or hemorrhagic cystitis instead. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:182px"> Low </td> </tr> </tbody> </table> Okay sorry I read that the summary only needs to be provided for the KER step 5 way too late as it was hidden below the table. I highlighted the summary you would mark and only did that KER for quantitative understanding 😊   <table cellspacing="0" class="Table" style="border-collapse:collapse; border:none; margin-left:96px; width:542px"> <tbody> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:79px"> KER </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:281px"> Summary of Quantitative Understanding* </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:182px"> WOE call </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:79px"> KER 1  CYP450 upregulationà oxidative stress </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:281px"> Not required by rubric </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:182px"> High </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:79px"> KER 2 oxidative stress  à lipid peroxidation </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:281px"> Oxidative stress resulting in lipid peroxidation has been noted in many taxa from bacteria to humans and at many live stages. The only limitation seen was no standardized specific minimum level of oxidative stress across taxa has been determined to result in lipid peroxidation. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:182px"> High </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:79px"> KER 3 lipid peroxidation à acrolein accumulation </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:281px"> Not required by rubric </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:182px"> High </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:79px"> KER 4 acrolein accumulation  à chronic kidney disease </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:281px"> Not required by rubric </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:182px"> Low </td> </tr> </tbody> </table> A. The overall domain of this AOP is limited to organisms that have kidneys. This is due to the fact that all key events and their relationships except the AO (chronic kidney disease) can occur in any organism that has a lipid bilayer and CYP450's, thus is less restrictive than the AO.  B. The domain limiting KER is acrolein accumulation leading to chronic kidney disease and the domain limiting KE is chronic kidney disease.

Key Event chosen: Oxidative stress  Essentiality requires evidence that supports the notion that if a key event (KE) is knocked out or blocked that the downstream key events can not occur unless involved in another pathway. One KE that has strong evidence of essentiality is oxidative stress, many repair studies have demonstrated that the quenching of reactive oxygen species and as a result oxidative stress will result in the arrest and reduction of lipid peroxidation. One great and more recent repair mechanism example for oxidative stress is through the use of antioxidant nano constructs. One study that focuses on nano based drug delivery systems and conveys essentiality for this AOP was completed by Seongchan Kim in 2021. In this study, Sprague-Dawley rats were exposed to a known reactive oxygen species inducer- lipopolysaccharide and the resulting reactive oxygen species and MDA content was measured with and without normal or nano-N-acetyl cysteine (nano-NAC). It was seen that after lipopolysaccharide incubation, the levels of H2O2 were very high without NAC, significantly reduced with 200 mg of NAC, and very significantly reduced through the use of 200 mg nano-NAC. In addition to this, the lipid peroxidation marker, MDA showed the equivalent trend with and without normal and nano-NAC. This study went as far as to remove the stressor all together as an additional comparison group which revealed consistently low amounts of MDA and reactive oxygen species<cite> (Kim et al., 2021).</cite> Another interesting study explores the addition of a stressor known to induce oxidative stress in rats (restraint stress) and the addition of an antioxidant curcumin<cite> (Samarghandian et al., 2017)</cite>. In this study oxidative stress was induced and measured in rats for 1 hour for 21 days, following this the rats were administered curcumin in varying concentrations as a repair mechanism and the lipid peroxidation levels through malondialdehyde (MDA) were observed via thiobarbituric acid reactive substances (TBARS) . In addition, the amounts of reduced glutathione (GSH), as well as antioxidant enzyme activities superoxide dismutase (SOD) glutathione peroxidase (GPx), glutathione reductase (GR) and catalase (CAT) were measured in the brain, liver and kidney of the rats<cite> (Samarghandian et al., 2017). </cite>It was seen that as the concentration of antioxidant curcumin and antioxidants increased, the levels of MDA decreased and in addition to this in the absence of a stressor it was seen that levels of lipid peroxidation remained significantly low. As such, it was seen through this experiment that the repair of oxidative stress inhibited the down stream key event of lipid peroxidation.  A more traditional study of essentiality focuses on the administration of hexavalent chromium (Cr (VI)) to human L-02 hepatocytes and Sprague Dawley rats tandem to the reduction of generated ROS via vitamin C quenching<cite> (Zhong et al., 2017)</cite>. In this study, human hepatocytes were exposed to 0-16 uM of Cr (VI) while the total ROS and superoxide anion production was measured via CM-H2DCFDA and DHE fluorescent dyes respectively. As the concentration of Cr (VI) increased the amount of reactive oxygen species detected with both dyes also increased with a peak at 8 uM of Cr (VI). Furthermore, MDA was measured via a standard MDA kit and its abundance followed the same trend as the ROS. After administration of vitamin C, it was noted that both MDA and ROS levels were significantly reduced at 200 mg of vitamin C for cell lines and 500 mg/kg bw, in rats <cite>(Zhong et al., 2017)</cite>. The subsequent quenching of ROS by vitamin C demonstrates the repair mechanism required for oxidative stress, thus blocking the downstream path of lipid peroxidation as measured through MDA depletion.   WOE call: The weight of evidence call for the essentiality of this key event is High. This is because there are multiple bodies of direct evidence from specifically designed experimental studies that illustrate the essentiality of oxidative stress to this AOP through repair mechanisms.

<div> <table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>Influence or Outcome</th> <th>KER(s) involved</th> </tr> </thead> <tbody> <tr> <td> </td> <td> </td> <td> </td> </tr> </tbody> </table> </div>

- Please note that this pathway must be chronically induced to lead to chronic kidney disease  - There are limitations to this AOP as the mechanism of toxicity by acrolein induced ER-stress is not well known.  - There are many CYP450 enzymes, some can activate this pathway but not all depending on their to activity, active site, conformation, and location .

Not Specified

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