25812-30-0 HEMJJKBWTPKOJG-UHFFFAOYSA-N HEMJJKBWTPKOJG-UHFFFAOYSA-N Gemfibrozil Pentanoic 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)- DTXSID0020652 41859-67-0 IIBYAHWJQTYFKB-UHFFFAOYSA-N IIBYAHWJQTYFKB-UHFFFAOYSA-N Bezafibrate Propanoic acid, 2-[4-[2-[(4-chlorobenzoyl)amino]ethyl]phenoxy]-2-methyl- Befizal Benzofibrate Bezafibrat bezafibrato Bezalip Bezatol Difaterol DTXSID3029869 637-07-0 KNHUKKLJHYUCFP-UHFFFAOYSA-N KNHUKKLJHYUCFP-UHFFFAOYSA-N Clofibrate ethyl-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 DTXSID3020336 49562-28-9 YMTINGFKWWXKFG-UHFFFAOYSA-N YMTINGFKWWXKFG-UHFFFAOYSA-N Fenofibrate Propanoic 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 DTXSID2029874 134523-00-5 XUKUURHRXDUEBC-KAYWLYCHSA-N XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Cardyl Atorvastatin acid 1H-Pyrrole-1-heptanoic acid, 2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-, (βR,δR)- DTXSID8029868 79902-63-9 RYMZZMVNJRMUDD-HGQWONQESA-N RYMZZMVNJRMUDD-HGQWONQESA-N Simvastatin Butanoic 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 DTXSID0023581 PR:000008636 PR 3-hydroxy-3-methylglutaryl-coenzyme A reductase CHEBI:25350 CHEBI mevalonate CHEBI:16113 CHEBI cholesterol CHEBI:17002 CHEBI cholesteryl ester CHEBI:17347 CHEBI testosterone UBERON:0000079 UBERON male reproductive system D005298 MESH fertility GO:0042282 GO hydroxymethylglutaryl-CoA reductase activity GO:0006695 GO cholesterol biosynthetic process GO:0030301 GO cholesterol transport 2 WIKI decreased 8 WIKI morphological change Gemfibrozil <p>Fibrate drug</p> 2016-11-29T18:42:27 2020-03-31T10:24:40 Bezafibrate 2016-11-29T18:42:27 2016-11-29T18:42:27 Clofibrate 2016-11-29T18:42:27 2016-11-29T18:42:27 Fenofibrate 2016-11-29T18:42:27 2016-11-29T18:42:27 Atorvastatin 2020-03-31T10:30:56 2020-03-31T10:30:56 Simvastatin 2020-05-06T09:41:35 2020-05-06T09:41:35 WikiUser_28 Vertebrates 10095 NCBI mice WCS_9606 common toxicological species human 10117 NCBI Rattus rattus Inhibition, HMG-CoA reductase Cellular <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> AOPWiki 2016-11-29T18:41:27 2016-12-03T16:33:28 Decreased, mevalonate Cellular AOPWiki 2016-11-29T18:41:27 2016-12-03T16:37:52 Decreased, cholesterol Tissue <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,&nbsp;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&rsquo;s used to produce steroid hormones (Azhar et al., 2007)</p> <p>Once cholesterol is produced in the liver, it&rsquo;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>&nbsp; ko04979</p> <p>&nbsp;</p> <p>Commerical assay kits are available for measuring cholesterol using either colorimetric&nbsp;or&nbsp;fluorometric&nbsp;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>,&nbsp;<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>).&nbsp;</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&nbsp;(Zhou et al., 2015).&nbsp;</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&nbsp;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:0001969 UBERON blood plasma High Male High Female High Adult Moderate All life stages High <p>Al-Habsi, A.A., A. Massarsky, T.W. Moon (2016) &ldquo;Exposure to gemfibrozil and atorvastatin affects cholesterol metabolism and steroid production in zebrafish (<em>Danio rerio</em>)&rdquo;, <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) &ldquo;Regulation of Leydig cell cholesterol metabolism&rdquo;, 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, Garc&iacute;a-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.&nbsp;Available from: https://www.ncbi.nlm.nih.gov/books/NBK351/</p> <p>Dai, W. et al. (2015) &quot;High fat plus high cholesterol diet lead to hepatic steatosis in zebrafish larvae: a novel model for screening anti-hepatic steatosis drugs&quot;,&nbsp;<em>Nutrition and Metabolism</em>, Vol. 12(42), Springer Nature.&nbsp;DOI 10.1186/s12986-015-0036-z&nbsp;</p> <p>Du, Z.Y. et al. (2008) &ldquo;Hypolipidaemic effect of fenofibrate and fasting in the herbivorous grass carp (<em>Ctenopharyngodon idella) </em>fed a high-fat diet&rdquo;, <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) &ldquo;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&rdquo;, <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., ... &amp; Fernandes, P. A. (2016). Cholesterol biosynthesis: a mechanistic overview.&nbsp;<em>Biochemistry</em>,&nbsp;<em>55</em>(39), 5483-5506.</p> <p>Prindiville, J.S. et al. (2011) &ldquo;The fibrate drug gemfibrozil disrupts lipoprotein metabolism in rainbow trout&rdquo;, <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.&nbsp;<em>Cellular and molecular life sciences CMLS</em>,&nbsp;<em>63</em>(10), 1165-1178.</p> <p>Risley, J. M. (2002). Cholesterol biosynthesis: Lanosterol to cholesterol.&nbsp;<em>Journal of chemical education</em>,&nbsp;<em>79</em>(3), 377.</p> <p>Sonawane, P.D. et al. (2016) &ldquo;Plant cholesterol biosynthetic pathway overlaps with phytosterol metabolism&rdquo;, <em>Nature Plants, </em>Vol. 3, Nature Publishing Group, https://doi.org/10.1038/nplants.2016.205</p> <p>Velasco-Santamar&iacute;a, Y.M. et al. (2011) &ldquo;Bezafibrate, a lipid-lowering pharmaceutical, as a potential endocrine disruptor in male zebrafish (<em>Danio rerio</em>)&rdquo;, <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) &ldquo;Evolution of the cholesterol biosynthesis pathway in animals&rdquo;, <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) &quot;Rapid analysis of hypolipidemic drugs in a live zebrafish assay&quot;,&nbsp;<em>Journal of Pharmacological and Toxicological Methods,&nbsp;</em>Vol. 72, Elsevier, pp. 47-52.&nbsp;http://dx.doi.org/10.1016/j.vascn.2014.12.002</p> AOPWiki 2016-11-29T18:41:27 2022-05-24T11:10:52 Decreased, Testosterone Individual AOPWiki 2016-11-29T18:41:27 2016-12-03T16:37:52 malformed, Male reproductive tract Individual UBERON:0000079 UBERON male reproductive system AOPWiki 2016-11-29T18:41:27 2017-09-16T10:16:27 Decrease, Fertility Individual High High AOPWiki 2016-11-29T18:41:24 2017-06-29T08:09:15 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00005eb8a1c21240> AOPWiki 2016-11-29T18:41:35 2016-12-03T16:38:00 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00005eb8a24eeaf8> AOPWiki 2016-11-29T18:41:35 2016-12-03T16:38:00 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00005eb8a2cef5e0> AOPWiki 2016-11-29T18:41:35 2016-12-03T16:38:00 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00005eb8a2553de0> AOPWiki 2016-11-29T18:41:35 2016-12-03T16:38:00 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00005eb8a27e56d0> AOPWiki 2016-11-29T18:41:35 2016-12-03T16:38:00 HMGCR inhibition to male fertility Cataia Ives <p>Kellie Fay</p> BY-SA 1.29 1.0 <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> adjacent Not Specified High adjacent Not Specified Not Specified adjacent Not Specified Not Specified non-adjacent Not Specified Not Specified non-adjacent Not Specified Not Specified Not Specified Male Low Fetal Not 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). &quot;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.&quot; Toxicological Sciences.</p> AOPWiki 2016-11-29T18:41:16 2023-09-25T16:26:51