This AOP is licensed under the BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

AOP: 532

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE.  More help

CYP450 upregulation leads to Chronic kidney disease

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
CYP450 upregulation leads to Chronic kidney disease
The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help
Handbook Version v2.6

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Amanda Ameyaa-Sakyi

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Arthur Author   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Arthur Author

Coaches

This field is used to identify coaches who supported the development of the AOP.Each coach selected must be a registered author. More help

OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication.   More help
OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
This AOP was last modified on June 20, 2024 20:48

Revision dates for related pages

Page Revision Date/Time
CYP450 Upregulation June 20, 2024 21:01
Oxidative Stress March 08, 2024 12:28
Acrolein accumulation June 18, 2024 22:16
Chronic kidney disease June 16, 2024 00:04
Increased, Lipid peroxidation July 27, 2023 10:25
CYP450 Upregulation leads to Oxidative Stress June 04, 2024 21:32
Oxidative Stress leads to Chronic kidney disease June 04, 2024 21:34
Oxidative Stress leads to Increased, LPO June 20, 2024 20:55
Increased, LPO leads to Acrolein accumulation June 04, 2024 21:33
Acrolein accumulation leads to Chronic kidney disease June 04, 2024 21:33
Cyclophosphamide June 04, 2024 21:30
Acrolein September 28, 2021 08:23
Ifosfamide June 14, 2024 13:48

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

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.

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP.The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 2228 CYP450 Upregulation CYP450 Upregulation
KE 1392 Oxidative Stress Oxidative Stress
KE 1445 Increased, Lipid peroxidation Increased, LPO
KE 2229 Acrolein accumulation Acrolein accumulation
AO 1603 Chronic kidney disease Chronic kidney disease

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
Adults High

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help
Term Scientific Term Evidence Link
humans Homo sapiens High NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Mixed High

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

KER

Summary of Bio. Plausibility Evidence*

WOE call

KER 1

 CYP450 upregulationà oxidative stress

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.

High

KER 2

oxidative stress  à lipid peroxidation

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.

High

KER 3

lipid peroxidation à acrolein accumulation

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.

High

KER 4

acrolein accumulation  à chronic kidney disease

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.

Moderate

 

KER

Summary of Empirical Evidence*

WOE call

KER 1

 CYP450 upregulationà oxidative stress

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.

High

KER 2

oxidative stress  à lipid peroxidation

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.

High

KER 3

lipid peroxidation à acrolein accumulation

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.

High

KER 4

acrolein accumulation  à chronic kidney disease

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.

Low

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 😊

 

KER

Summary of Quantitative Understanding*

WOE call

KER 1

 CYP450 upregulationà oxidative stress

Not required by rubric

High

KER 2

oxidative stress  à lipid peroxidation

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.

High

KER 3

lipid peroxidation à acrolein accumulation

Not required by rubric

High

KER 4

acrolein accumulation  à chronic kidney disease

Not required by rubric

Low

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

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.  

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

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 (Kim et al., 2021).

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 (Samarghandian et al., 2017). 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 (Samarghandian et al., 2017). 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 (Zhong et al., 2017). 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 (Zhong et al., 2017). 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.  

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help
Modulating Factor (MF) Influence or Outcome KER(s) involved
     

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

- 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 .

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

List of the literature that was cited for this AOP. More help

Samarghandian S, Azimi-Nezhad M, Farkhondeh T, Samini F. (2017) Anti-oxidative effects of curcumin on immobilization-induced oxidative stress in rat brain, liver and kidney. Biomed Pharmacother. ;87:223-229. 

Kim, S., Kim, S.Y., Rho, S.J. et al. Biocompatible N-acetyl-nanoconstruct alleviates lipopolysaccharide-induced acute lung injury in vivo. Sci Rep 11, 22662 (2021).

Zhong X, Zeng M, Bian H, Zhong C, Xiao F. (2017) An evaluation of the protective role of vitamin C in reactive oxygen species-induced hepatotoxicity due to hexavalent chromium in vitro and in vivo. J Occup Med Toxicol, Jun 15;12:15.

CYP450 KE references:

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 sciences22(23)

Acrolein references 

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.

Chronic kidney disease references 

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 & research10(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. JAMA322(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