PharmGKB summary: very important pharmacogene information for cytochrome P450, family 2, subfamily C, polypeptide 8

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IntroductionCytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) is a phase I metabolizing enzyme that plays an integral role in the biotransformation of structurally diverse xenobiotics and endogenous compounds 1. CYP2C8 accounts for 7% of the CYP content in the liver and is expressed to a lesser extent in the kidney, adrenal gland, mammary gland, brain, ovary, uterus, and duodenum 2–5. Over the last decade, CYP2C8 has garnered increased attention following the elucidation of its crystal structure, identification of clinically relevant substrates and inhibitors, and characterization of functional CYP2C8 single nucleotide polymorphisms (SNPs). This PharmGKB summary discusses CYP2C8 and its pharmacogenomic importance. A fully interactive version of this short review, with links to individual paper annotations can be found at, inhibitors, and inducersCYP2C8 is responsible for the biotransformation of 5% of currently used drugs that undergo phase I hepatic metabolism 4. The enzyme’s substrate-binding cavity can accommodate large and structurally unrelated compounds (e.g. paclitaxel and amiodarone) 6,7. In addition, the CYP2C8 active site is similar in size, but different in shape, from that of CYP3A4 6,8. This likely explains why CYP2C8 and CYP3A4 often have overlapping substrates, but yield different metabolite profiles 4,9.Table 1 provides a list of drugs for which CYP2C8 is a major contributor to metabolism. CYP2C8 also plays an intermediate or minor role in the oxidation of myriad other xenobiotics and endogenous compounds such as NSAIDs (e.g. ibuprofen and diclofenac) 24,25, statins (e.g. fluvastatin and simvastatin acid) 26,27, calcium channel blockers (e.g. verapamil) 28,29, opioids (e.g. morphine and methadone) 30,31, tyrosine kinase inhibitors (e.g. imatinib) 32,33, arachidonic acid 34,35, retinoids 36–39, and others. Further information on CYP2C8 substrates is provided at and in comprehensive reviews 4,23,40.In vitro, many compounds have been shown to inhibit CYP2C8 including gemfibrozil, trimethoprim, ketoconazole, montelukast, quercetin, and others 14,16,41–46. In vivo, gemfibrozil is the most potent CYP2C8 inhibitor, primarily because of rapid, mechanism-based inactivation of CYP2C8 by its 1-O-β glucuronide metabolite 47–51. In clinical studies, gemfibrozil has been shown to increase the plasma exposure of CYP2C8 substrates such as rosiglitazone 52, pioglitazone 53,54, repaglinide 55–57, cerivastatin 58, loperamide 59, R-ibuprofen 60, and montelukast 61. In addition, gemfibrozil reduced imatinib metabolite formation in healthy volunteers 62.CYP2C8 has been described as the most inducible member of the CYP2C subfamily 4,40. Transcriptional activation of CYP2C8 is mediated by the pregnane X receptor (NR1I2), the constitutive androstane receptor (NR1I3), and the glucocorticoid receptor (NR3C1) 63,64. Along these lines, a constitutive androstane receptor/pregnane X receptor-binding sequence in the distal promoter (−8806 bp) is thought to play a key role in CYP2C8 induction 63. In vitro, CYP2C8 is upregulated by the inducers rifampin (rifampicin), dexamethasone, and phenobarbital 65–68. In clinical drug–drug interaction studies, rifampin has been shown to decrease the plasma exposure of major CYP2C8 substrates such as rosiglitazone 69,70, pioglitazone 71, and repaglinide 72,73.CYP2C8 gene and common variantsCYP2C8 is located on chromosome 10q24 in a CYP2C gene cluster (centromere–CYP2C18CYP2C19CYP2C9CYP2C8–telomere), of which CYP2C8 is the smallest gene (31 kb, nine exons) 5,74,75. Given the close proximity of CYP2C8 and CYP2C9, some linkage disequilibrium exists between these genes 76. Substantial interindividual variability exists in CYP2C8 protein expression and catalytic activity 18,77,78. This variability is due, in part, to genetic polymorphisms. Over 450 CYP2C8 SNPs have been identified to date 40.

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