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{{Short description|Gene-coded protein involved in metabolism of xenobiotics}}{{cs1 config|name-list-style=vanc}}

factoids

Cytochrome P4502C8 (CYP2C8) is a member of the cytochrome P450 mixed-function oxidase system involved in the metabolism of xenobiotics in the body. Cytochrome P4502C8 also possesses epoxygenase activity, i.e. it metabolizes long-chain polyunsaturated fatty acids, e.g. arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, and Linoleic acid to their biologically active epoxides.JOURNAL, Westphal C, Konkel A, Schunck WH, CYP-eicosanoids--a new link between omega-3 fatty acids and cardiac disease?, Prostaglandins & Other Lipid Mediators, 96, 1–4, 99–108, Nov 2011, 21945326, 10.1016/j.prostaglandins.2011.09.001,

Ligands

Following is a table of selected substrates, inducers and inhibitors of 2C8.Inhibitors of CYP2C8 can be classified by their potency, such as:

• Strong inhibitor being one that causes at least a five-fold increase in the plasma AUC values, or more than 80% decrease in clearance.
• Moderate inhibitor being one that causes at least a two-fold increase in the plasma AUC values, or 50-80% decrease in clearance.
• Weak inhibitor being one that causes at least a 1.25-fold but less than two-fold increase in the plasma AUC values, or 20-50% decrease in clearance.WEB, Flockhart DA, Drug Interactions: Cytochrome P450 Drug Interaction Table, Indiana University School of Medicine, 2007,weblink Retrieved on July 2011

{| class="wikitable"|+Selected inducers, inhibitors and substrates of CYP2C8! Substrates !! Inhibitors !! Inducers style="vertical-align: top;"|

• amodiaquine (antimalarial, anti-inflammatory)
• cerivastatin (statin)
• enzalutamide (antiandrogen)
• paclitaxel (chemotherapeutic)
• repaglinide (antidiabetic)
• torasemide (loop diuretic)
• sorafenib (tyrosine kinase inhibitor)
• rosiglitazone (antidiabetic) - converted to active metabolitesChapter 26 in: BOOK, Rod Flower, Humphrey P. Rang, Maureen M. Dale, Ritter, James M., Rang & Dale's pharmacology, Churchill Livingstone, Edinburgh, 2007, 978-0-443-06911-6,
• buprenorphine (semisynthetic opioid)
• polyunsaturated fatty acids
• montelukast (leukotriene receptor antagonist)

Strong gemfibrozil (hypolipidemic) the acyl-β-glucuronide metabolite of clopidogrelProduct Information: PLAVIX(R) oral tablets, clopidogrel bisulfate oral tablets. Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership (per FDA), Bridgewater, NJ, 2019. weblink {{Webarchive|url=https://web.archive.org/web/20210612191932weblink |date=2021-06-12 }} (antiplatelet) Moderate trimethoprim (antibiotic) Unspecified potency thiazolidinediones (antidiabetic) montelukast (leukotriene receptor antagonist) quercetin (antiinflammatory)

Unspecified potency rifampicin (antibiotic)

Where classes of agents are listed, there may be exceptions within the class.

Epoxygenase activity

CYP2C8 also possesses epoxygenase activity: it is one of the principal enzymes responsible for attacking various long-chain polyunsaturated fatty acids at their double (i.e. alkene) bonds to form epoxide products that act as signaling agents. It metabolizes: 1) arachidonic acid to various epoxyeicosatrienoic acids (also termed EETs); 2) linoleic acid to 9,10-epoxy octadecenoic acids (also termed vernolic acid, linoleic acid 9:10-oxide, or leukotoxin) and 12,13-epoxy-octadecenoic (also termed coronaric acid, linoleic acid 12,13-oxide, or isoleukotoxin); 3) docosahexaenoic acid to various epoxydocosapentaenoic acids (also termed EDPs); and 4) eicosapentaenoic acid to various epoxyeicosatetraenoic acids (also termed EEQs).JOURNAL, Fleming I, The pharmacology of the cytochrome P450 epoxygenase/soluble epoxide hydrolase axis in the vasculature and cardiovascular disease, Pharmacological Reviews, 66, 4, 1106–40, October 2014, 25244930, 10.1124/pr.113.007781, 39465144, JOURNAL, Wagner K, Vito S, Inceoglu B, Hammock BD, The role of long chain fatty acids and their epoxide metabolites in nociceptive signaling, Prostaglandins & Other Lipid Mediators, 113-115, 2–12, October 2014, 25240260, 10.1016/j.prostaglandins.2014.09.001, 4254344, JOURNAL, Fischer R, Konkel A, Mehling H, Blossey K, Gapelyuk A, Wessel N, von Schacky C, Dechend R, Muller DN, Rothe M, Luft FC, Weylandt K, Schunck WH, Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway, Journal of Lipid Research, 55, 6, 1150–1164, March 2014, 24634501, 10.1194/jlr.M047357, free, 4031946, Along with CYP2C8, CYP2C9, CYP2C19, CYP2J2, and possibly CYP2S1 are the main producers of EETs and, very likely, EEQs, EDPs, and the epoxides of linoleic acid.JOURNAL, Spector AA, Kim HY, Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism, Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 1851, 4, 356–65, April 2015, 25093613, 10.1016/j.bbalip.2014.07.020, 4314516, JOURNAL, Shahabi P, Siest G, Meyer UA, Visvikis-Siest S, Human cytochrome P450 epoxygenases: variability in expression and role in inflammation-related disorders, Pharmacology & Therapeutics, 144, 2, 134–61, November 2014, 24882266, 10.1016/j.pharmthera.2014.05.011,

See also

• Cytochrome P450 oxidase
• Epoxygenase

References

{{reflist|33em}}

External links

• {{UCSC gene info|CYP2C8}}

Further reading

• JOURNAL, Goldstein JA, de Morais SM, Biochemistry and molecular biology of the human CYP2C subfamily, Pharmacogenetics, 4, 6, 285–99, Dec 1994, 7704034, 10.1097/00008571-199412000-00001,
• JOURNAL, Smith G, Stubbins MJ, Harries LW, Wolf CR, Molecular genetics of the human cytochrome P450 monooxygenase superfamily, Xenobiotica, 28, 12, 1129–65, Dec 1998, 9890157, 10.1080/004982598238868,
• JOURNAL, García-Martín E, Martínez C, Ladero JM, Agúndez JA, Interethnic and intraethnic variability of CYP2C8 and CYP2C9 polymorphisms in healthy individuals, Molecular Diagnosis & Therapy, 10, 1, 29–40, 2007, 16646575, 10.1007/BF03256440, 25261882,
• JOURNAL, Ged C, Beaune P, Isolation of the human cytochrome P-450 IIC8 gene: multiple glucocorticoid responsive elements in the 5' region, Biochimica et Biophysica Acta, 1088, 3, 433–5, Mar 1991, 1707679, 10.1016/0167-4781(91)90138-c,
• JOURNAL, Romkes M, Faletto MB, Blaisdell JA, Raucy JL, Goldstein JA, Cloning and expression of complementary DNAs for multiple members of the human cytochrome P450IIC subfamily, Biochemistry, 30, 13, 3247–55, Apr 1991, 2009263, 10.1021/bi00227a012,
• JOURNAL, Kolyada AY, Sequence of a human liver cytochrome P-450 cDNA clone, Nucleic Acids Research, 18, 18, 5550, Sep 1990, 2216732, 332242, 10.1093/nar/18.18.5550,
• JOURNAL, Shephard EA, Phillips IR, Santisteban I, Palmer CN, Povey S, Cloning, expression and chromosomal localization of a member of the human cytochrome P450IIC gene sub-family, Annals of Human Genetics, 53, Pt 1, 23–31, Jan 1989, 2729895, 10.1111/j.1469-1809.1989.tb01119.x, 32620206,
• JOURNAL, Ged C, Umbenhauer DR, Bellew TM, Bork RW, Srivastava PK, Shinriki N, Lloyd RS, Guengerich FP, Characterization of cDNAs, mRNAs, and proteins related to human liver microsomal cytochrome P-450 (S)-mephenytoin 4'-hydroxylase, Biochemistry, 27, 18, 6929–40, Sep 1988, 3196692, 10.1021/bi00418a039,
• JOURNAL, Okino ST, Quattrochi LC, Pendurthi UR, McBride OW, Tukey RH, Characterization of multiple human cytochrome P-450 1 cDNAs. The chromosomal localization of the gene and evidence for alternate RNA splicing, The Journal of Biological Chemistry, 262, 33, 16072–9, Nov 1987, 10.1016/S0021-9258(18)47697-1, 3500169, free,
• JOURNAL, Harry Gelboin, Kimura S, Pastewka J, Gelboin HV, Gonzalez FJ, cDNA and amino acid sequences of two members of the human P450IIC gene subfamily, Nucleic Acids Research, 15, 23, 10053–4, Dec 1987, 3697070, 306558, 10.1093/nar/15.23.10053,
• JOURNAL, John R. Falck, Zeldin DC, DuBois RN, Falck JR, Capdevila JH, Molecular cloning, expression and characterization of an endogenous human cytochrome P450 arachidonic acid epoxygenase isoform, Archives of Biochemistry and Biophysics, 322, 1, 76–86, Sep 1995, 7574697, 10.1006/abbi.1995.1438,
• JOURNAL, Inoue K, Inazawa J, Suzuki Y, Shimada T, Yamazaki H, Guengerich FP, Abe T, Fluorescence in situ hybridization analysis of chromosomal localization of three human cytochrome P450 2C genes (CYP2C8, 2C9, and 2C10) at 10q24.1, The Japanese Journal of Human Genetics, 39, 3, 337–43, Sep 1994, 7841444, 10.1007/BF01874052, free,
• JOURNAL, Gray IC, Nobile C, Muresu R, Ford S, Spurr NK, A 2.4-megabase physical map spanning the CYP2C gene cluster on chromosome 10q24, Genomics, 28, 2, 328–32, Jul 1995, 8530044, 10.1006/geno.1995.1149,
• JOURNAL, Wormhoudt LW, Ploemen JH, de Waziers I, Commandeur JN, Beaune PH, van Bladeren PJ, Vermeulen NP, Inter-individual variability in the oxidation of 1,2-dibromoethane: use of heterologously expressed human cytochrome P450 and human liver microsomes, Chemico-Biological Interactions, 101, 3, 175–92, Sep 1996, 8870687, 10.1016/0009-2797(96)03723-4, 1996CBI...101..175W,
• JOURNAL, McFayden MC, Melvin WT, Murray GI, Regional distribution of individual forms of cytochrome P450 mRNA in normal adult human brain, Biochemical Pharmacology, 55, 6, 825–30, Mar 1998, 9586955, 10.1016/S0006-2952(97)00516-9,
• JOURNAL, Macé K, Bowman ED, Vautravers P, Shields PG, Harris CC, Pfeifer AM, Characterisation of xenobiotic-metabolising enzyme expression in human bronchial mucosa and peripheral lung tissues, European Journal of Cancer, 34, 6, 914–20, May 1998, 9797707, 10.1016/S0959-8049(98)00034-3,
• JOURNAL, Klose TS, Blaisdell JA, Goldstein JA, Gene structure of CYP2C8 and extrahepatic distribution of the human CYP2Cs, Journal of Biochemical and Molecular Toxicology, 13, 6, 289–95, 1999, 10487415, 10.1002/(SICI)1099-0461(1999)13:63.0.CO;2-N, 25926848,weblink
• JOURNAL, Finta C, Zaphiropoulos PG, The human CYP2C locus: a prototype for intergenic and exon repetition splicing events, Genomics, 63, 3, 433–8, Feb 2000, 10704292, 10.1006/geno.1999.6063,

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