25812-30-0HEMJJKBWTPKOJG-UHFFFAOYSA-NHEMJJKBWTPKOJG-UHFFFAOYSA-N
GemfibrozilPentanoic acid, 5-(2,5-dimethylphenoxy)-2,2-dimethyl-
2,2-Dimethyl-5-(2,5-xylyloxy)valeric acid
5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoic acid
Decrelip
gemfibrozilo
Gevilon
Lopizid
Trialmin 900
Valeric acid, 2,2-dimethyl-5-(2,5-xylyloxy)-
DTXSID002065241859-67-0IIBYAHWJQTYFKB-UHFFFAOYSA-NIIBYAHWJQTYFKB-UHFFFAOYSA-N
BezafibratePropanoic acid, 2-[4-[2-[(4-chlorobenzoyl)amino]ethyl]phenoxy]-2-methyl-
Befizal
Benzofibrate
Bezafibrat
bezafibrato
Bezalip
Bezatol
Difaterol
DTXSID3029869637-07-0KNHUKKLJHYUCFP-UHFFFAOYSA-NKNHUKKLJHYUCFP-UHFFFAOYSA-N
Clofibrateethyl-p-chlorophenoxyisobutyrate
Propanoic acid, 2-(4-chlorophenoxy)-2-methyl-, ethyl ester
2-(p-Chlorophenoxy)-2-methylpropionic acid ethyl ester
Abitrate
Amotril
Anparton
Arteriosan
Artevil
Ateculon
Ateriosan
Atheropront
Atromid S
Atromidin
Azionyl
Bioscleran
Cartagyl
Claripex
Claripex CPIB
Clobren SF
Clofibrat
clofibrato
Clofinit
Ethyl (p-chlorophenoxy) isobutyrate
Ethyl 2-(4-chlorophenoxy)-2-methylpropionate
Ethyl 2-(4-chlorophenoxy)isobutyrate
Ethyl 2-(p-chlorophenoxy)-2-methylpropionate
Ethyl 2-(p-chlorophenoxy)isobutyrate
Ethyl clofibrate
Ethyl p-chlorophenoxyisobutyrate
Ethyl α-(4-chlorophenoxy)isobutyrate
Ethyl α-(4-chlorophenoxy)-α-methylpropionate
Ethyl α-(p-chlorophenoxy)isobutyrate
Ethyl α-(p-chlorophenoxy)-α-methylpropionate
Hyclorate
Lipavil
Lipavlon
Lipomid
Liprinal
Miscleron
Misclerone
Neo-Atromid
Normolipol
NSC 79389
p-Chlorophenoxyisobutyric acid ethyl ester
Propionic acid, 2-(p-chlorophenoxy)-2-methyl-, ethyl ester
Recolip
Regelan
Serotinex
Sklerepmexe
Sklerolip
Skleromexe
Sklero-Tablinene
Ticlobran
Xyduril
DTXSID302033649562-28-9YMTINGFKWWXKFG-UHFFFAOYSA-NYMTINGFKWWXKFG-UHFFFAOYSA-N
FenofibratePropanoic acid, 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-, 1-methylethyl ester
2-[4-(4-Chlorobenzoyl)phenoxy]-2-methylpropanoic acid 1-methylethyl ester
Ankebin
Clorofibrate
Elasterin
Fenobrate
Fenofibrat
fenofibrato
Fenogal
Fenotard
Isopropyl 2-[p-(p-chlorobenzoyl)phenoxy]-2-methylpropionate
Lipanthyl
Lipantil
Lipicard
Lipidil
Lipidil Supra
Lipirex
Lipoclar
Lipofene
Liposit
MeltDose
Nolipax
NSC 281319
Procetofen
Procetofene
Procetoken
Protolipan
Secalip
DTXSID2029874134523-00-5XUKUURHRXDUEBC-KAYWLYCHSA-NXUKUURHRXDUEBC-KAYWLYCHSA-N
AtorvastatinCardyl
Atorvastatin acid
1H-Pyrrole-1-heptanoic acid, 2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-, (βR,δR)-
DTXSID802986879902-63-9RYMZZMVNJRMUDD-HGQWONQESA-NRYMZZMVNJRMUDD-HGQWONQESA-N
SimvastatinButanoic acid, 2,2-dimethyl-, (1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1-naphthalenyl ester
(+)-Simvastatin
Apo-Simvastatin
Bestatin 20
Butanoic acid, 2,2-dimethyl-, 1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl ester, [1S-[1α,3α,7β,8β(2S*,4S*),8aβ]]-
Cholestat
Co-Simvastatin
Kolestevan
L 644128-000U
Lipinorm
Liponorm
Lipovas
Lodales
Modutrol
Nor-Vastina
Novo-Simvastatin
Pms-simvastatin
Simastin 20
Simovil
Simvastatin lactone
Simvotin
Sinvacor
Sinvascor
Sivastin
Starstat 20
Synvinolin
Valemia
Velostatin
DTXSID0023581PR:0000086363-hydroxy-3-methylglutaryl-coenzyme A reductaseCHEBI:25350mevalonateCHEBI:16113cholesterolCHEBI:17002cholesteryl esterCHEBI:17347testosteroneUBERON:0000079male reproductive systemD005298fertilityGO:0042282hydroxymethylglutaryl-CoA reductase activityGO:0006695cholesterol biosynthetic processGO:0030301cholesterol transport2decreased8morphological changeGemfibrozil<p>Fibrate drug</p>
2016-11-29T18:42:272020-03-31T10:24:40Bezafibrate2016-11-29T18:42:272016-11-29T18:42:27Clofibrate2016-11-29T18:42:272016-11-29T18:42:27Fenofibrate2016-11-29T18:42:272016-11-29T18:42:27Atorvastatin2020-03-31T10:30:562020-03-31T10:30:56Simvastatin2020-05-06T09:41:352020-05-06T09:41:35WikiUser_28Vertebrates10095miceWCS_9606human10117Rattus rattusInhibition, HMG-CoA reductaseInhibition, HMG-CoA reductaseCellular<p>The activity of HMG-CoA reductase inhibition may be measured by a commercially available kit which measures a decrease in absorbance at 340 nm, which represents the oxidation of NADPH by the catalytic subunit of HMGR in the presence of the substrate HMG-CoA. Sterol Regulatory element-binding factor 1 (SREBF) is the transcription factor controlling downstream regulation of HMG-CoA reductase. The ToxCast assay ATG_SREBF1_CIS_up is one method of measuring transcriptional control of HMG-CoA reductase.
<em>
</em>
</p>2016-11-29T18:41:272016-12-03T16:33:28Decreased, mevalonateDecreased, mevalonateCellular2016-11-29T18:41:272016-12-03T16:37:52Decreased, cholesterolDecreased, cholesterolTissue<p>Most cholesterol synthesis in vertebrates occurs within the endoplasmic reticulum of hepatic cells. First, acetyl-CoA is converted to HMG-CoA via HMG-CoA synthase. Next, HMG-CoA is converted to mevalonate via HMG-CoA reductase. Several other steps follow, but conversion of HMG-CoA to mevalonate is the rate-limiting step of cholesterol synthesis (Cerqueira et al. 2016; Risley 2002). Consequently, Statin drugs inhibit HMG-CoA reductase to reduce cholesterol (Pahan 2006).</p>
<p>Cholesterol synthesis may also occur to a limited extent in steroidogenic cells where it’s used to produce steroid hormones (Azhar et al., 2007)</p>
<p>Once cholesterol is produced in the liver, it’s transported in the plasma. Hydrophobic lipids like cholesterol, cholesteryl ester (a cholesterol molecule bound to a fatty acid), and triglycerides are transported via lipoprotein complexes. There are different groups of lipoproteins which use different proteins and ratios of lipids including high-density lipoprotein (HDL), low-density (LDL), and very low-density (VLDL).</p>
<p><a href="https://www.genome.jp/pathway/ko04979+K05641">Cholesterol metabolism KEGG Pathway</a> ko04979</p>
<p> </p>
<p>Commerical assay kits are available for measuring cholesterol using either colorimetric or fluorometric detection. Total cholesterol assay kits often include cholesteryl esters in the measurement (<a href="https://www.cellbiolabs.com/total-cholesterol-assay-kit">Cell Bio Labs</a>, <a href="https://www.thermofisher.com/order/catalog/product/A12216#/A12216">ThermoFisher</a>). Additional kits are availalbe for measuring the cholesterol in the different lipoprotein complexes (<a href="https://www.cellbiolabs.com/hdl-and-ldlvldl-cholesterol-assay-kit">Cell Bio Labs</a>). </p>
<p>Oil Red O staining can be used for organisms such as zebrafish larvae that are clear, however it stains triglycerides and lipids not just cholesterol (Zhou et al., 2015). </p>
<p>Plasma cholesterol is a common clinical measurement in humans and the Abell-Kendall technique is the standard chemical determination method (Cox et al. 1990), although there are a wide variety of viable methods.</p>
<p>Taxonomic Applicability: Cholesterol is synthesized in plants but acts as a precursor for different products than in animals (Sonawane et al. 2016). Within the animal kingdom most deuterostomes (including vertebrata, cyclostomata, cephalochordate, and echinodermata, but not chordata) possess the genes necessary for cholesterol biosynthesis. However, most protostomes (including arthropoda and nematomorpha) have lost these genes (Zhang et al., 2019). Thus far vertebrates are the primary consideration for this KE.</p>
<p>Lifestage Applicability: Cholesterol can be measured in organisms at all life stages. However, the size of young organisms may limit the ability to collect plasma for cholesterol analysis. Whole-body measurements or pooled samples may be more feasible.</p>
<p>Sex Applicability: Cholesterol measurements are applicable for all sexes</p>
UBERON:0001969blood plasmaHighMaleHighFemaleHighAdultModerateAll life stagesHigh<p>Al-Habsi, A.A., A. Massarsky, T.W. Moon (2016) “Exposure to gemfibrozil and atorvastatin affects cholesterol metabolism and steroid production in zebrafish (<em>Danio rerio</em>)”, <em>Comparative Biochemistry and Physiology, Part B, </em>Vol. 199, Elsevier, pp. 87-96. http://dx.doi.org/10.1016/j.cbpb.2015.11.009</p>
<p>Azhar, S., E. Reaven (2007) “Regulation of Leydig cell cholesterol metabolism”, in A.H. Payne, M.P. Hardy (eds.) <em>The Leydig Cell in Health and Disease, </em>Humana Press. https://doi.org/10.1007/978-1-59745-453-7</p>
<p>Cox RA, García-Palmieri MR. Cholesterol, Triglycerides, and Associated Lipoproteins. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990. Chapter 31. Available from: https://www.ncbi.nlm.nih.gov/books/NBK351/</p>
<p>Dai, W. et al. (2015) "High fat plus high cholesterol diet lead to hepatic steatosis in zebrafish larvae: a novel model for screening anti-hepatic steatosis drugs", <em>Nutrition and Metabolism</em>, Vol. 12(42), Springer Nature. DOI 10.1186/s12986-015-0036-z </p>
<p>Du, Z.Y. et al. (2008) “Hypolipidaemic effect of fenofibrate and fasting in the herbivorous grass carp (<em>Ctenopharyngodon idella) </em>fed a high-fat diet”, <em>British Journal of Nutrition, </em>Vol. 100, Cambridge University Press, pp. 1200-1212. doi:10.1017/S0007114508986840</p>
<p>Guo, X. et al. (2015) “Effects of lipid-lowering pharmaceutical clofibrate on lipid and lipoprotein metabolism of grass carp (<em>Ctenopharyngodon idellal </em>Val.) fed with the high non-protein energy diets”, <em>Fish Physiology and Biochemistry, </em>Vol. 41, Springer, pp. 331-343. doi: 10.1007/s10695-014-9986-8</p>
<p>Cerqueira, N. M., Oliveira, E. F., Gesto, D. S., Santos-Martins, D., Moreira, C., Moorthy, H. N., ... & Fernandes, P. A. (2016). Cholesterol biosynthesis: a mechanistic overview. <em>Biochemistry</em>, <em>55</em>(39), 5483-5506.</p>
<p>Prindiville, J.S. et al. (2011) “The fibrate drug gemfibrozil disrupts lipoprotein metabolism in rainbow trout”, <em>Toxicology and Applied Pharmacology, </em>Vol. 251, Elsevier, pp. 201-238. doi:10.1016/j.taap.2010.12.013</p>
<p>Pahan, K. (2006). Lipid-lowering drugs. <em>Cellular and molecular life sciences CMLS</em>, <em>63</em>(10), 1165-1178.</p>
<p>Risley, J. M. (2002). Cholesterol biosynthesis: Lanosterol to cholesterol. <em>Journal of chemical education</em>, <em>79</em>(3), 377.</p>
<p>Sonawane, P.D. et al. (2016) “Plant cholesterol biosynthetic pathway overlaps with phytosterol metabolism”, <em>Nature Plants, </em>Vol. 3, Nature Publishing Group, https://doi.org/10.1038/nplants.2016.205</p>
<p>Velasco-Santamaría, Y.M. et al. (2011) “Bezafibrate, a lipid-lowering pharmaceutical, as a potential endocrine disruptor in male zebrafish (<em>Danio rerio</em>)”, <em>Aquatic Toxicology, </em>Vol. 105, Elsevier, pp. 107-118. doi:10.1016/j.aquatox.2011.05.018</p>
<p>Zhang, T. et al. (2019) “Evolution of the cholesterol biosynthesis pathway in animals”, <em>Molecular Biology and Evolution, </em>Vol. 36(11), Oxford University Press, pp. 2548-2556. doi:10.1093/molbev/msz167</p>
<p>Zhou, J. et al. (2015) "Rapid analysis of hypolipidemic drugs in a live zebrafish assay", <em>Journal of Pharmacological and Toxicological Methods, </em>Vol. 72, Elsevier, pp. 47-52. http://dx.doi.org/10.1016/j.vascn.2014.12.002</p>
2016-11-29T18:41:272022-05-24T11:10:52Decreased, TestosteroneDecreased, TestosteroneIndividual2016-11-29T18:41:272016-12-03T16:37:52malformed, Male reproductive tractmalformed, Male reproductive tractIndividualUBERON:0000079male reproductive system2016-11-29T18:41:272017-09-16T10:16:27Decrease, FertilityDecrease, FertilityIndividualHighHigh2016-11-29T18:41:242017-06-29T08:09:15a03f1603-336d-421e-a97e-2713cef7b5d48c99a11f-9619-429c-9500-7f4b041cd4702016-11-29T18:41:352016-12-03T16:38:008c99a11f-9619-429c-9500-7f4b041cd470a5869d68-cd26-4e5b-9bee-5c2465e35ce82016-11-29T18:41:352016-12-03T16:38:00a5869d68-cd26-4e5b-9bee-5c2465e35ce8a9414bd8-1ce6-447a-9ee2-d8d79b9d99bb2016-11-29T18:41:352016-12-03T16:38:00a9414bd8-1ce6-447a-9ee2-d8d79b9d99bb36a89c3b-68b8-49e9-9159-e5b1994d7deb2016-11-29T18:41:352016-12-03T16:38:0036a89c3b-68b8-49e9-9159-e5b1994d7deb6280e07f-2238-45eb-84a6-94d09e0d826c2016-11-29T18:41:352016-12-03T16:38:00HMG-CoA reductase inhibition leading to decreased fertilityHMGCR inhibition to male fertility<p>Kellie Fay</p>
Under Development: Contributions and Comments WelcomeUnder Development1.29<p>During sexual differentiation and gonadal development in utero or in ovo, androgenic tissues develop, in part, under the control of testosterone (Viger et al. 2005). Reduction of circulating testosterone during this crucial time of development can result in malformed reproductive tracts in males. Exposure to drugs (e.g., statins) or other compounds may cause male reproductive tract abnormalities by inhibiting HMG-CoA reductase, which is the rate-limiting enzyme in the production of cholesteron, the precursor of testosterone.</p>
adjacentNot SpecifiedHighadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot Specifiednon-adjacentNot SpecifiedNot Specifiednon-adjacentNot SpecifiedNot SpecifiedNot SpecifiedMaleLowFetalNot Specified<p>This AOP was developed primarily from one study of exposure of rats in utero to simvastatin (as well as a phthalate ester; Beverley et al., 2015) and biological plausibility. It currently should be considered putative and untested.</p>
<p>Beverly, B. E. J., et al. (2014). "Simvastatin and Dipentyl Phthalate Lower Ex Vivo Testicular Testosterone Production and Exhibit Additive Effects on Testicular Testosterone and Gene Expression Via Distinct Mechanistic Pathways in the Fetal Rat." Toxicological Sciences.</p>
2016-11-29T18:41:162023-04-29T13:02:12