Gene:

CYP2C9

cytochrome P450, family 2, subfamily C, polypeptide 9

CYP2C9 is a phase I drug-metabolizing cytochrome P450 (CYP450) enzyme isoform that plays a major role in the oxidation of both xenobiotic and endogenous compounds. Gray et al. [Article:8530044] identified CYP2C9 as one of several CYP2C genes clustered in a 500kb region on chromosome 10q24. The cluster comprises four genes arranged in the order CYP2C8-CYP2C9-CYP2C19-CYP2C18 [Article:8530044]. Several studies identified a single nucleotide polymorphism (SNP) linkage between the CYP2C8 and CYP2C9 genes [Articles:8530044, 12435384, 19381162]. CYP2C9 is primarily expressed in the liver, and the expression level is reported to be the second highest among CYP isoforms [Article:12580989]. Only the CYP enzyme CYP3A4 is quantitatively more highly expressed in human liver [Article:15822186]. It has been estimated that CYP2C9 is responsible for the metabolic clearance of up to 15%-20% of all drugs undergoing Phase I metabolism [Articles:19152219, 11927841].

Inducer and Inhibitors: CYP2C9 is induced by rifampicin [Article:19369937]. Treatment with rifampicin has been shown consistently to increase the clearance of drugs eliminated by CYP2C9. The clearance of losartan, phenytoin, tolbutamide and S-warfarin is approximately doubled in healthy volunteers or patients treated with rifampicin [Articles:9663807, 18650803]. CYP2C9 is inhibited by amiodarone, fluconazole, and sulphaphenazole among other drugs [Article:9663807]. Dangerous drug-drug interaction can arise when an inhibitor such as one of these is added to a therapeutic regime that include drugs with a low therapeutic index, such as S-warfarin, tolbutamine, and phenytoin [Articles:7944078, 8806399, 15963007]. For example, there are numerous studies documenting potentiation of the anticoagulant effect of warfarin in patients coadministered with amiodarone [Articles:18463344, 14677664, 1563209].

Structure: CYP2C9 is the enzyme responsible for the metabolism of the S-isomer of warfarin that is principally responsible for the anticoagulant effect of the drug. The crystal structure of human CYP2C9 was described by Williams et al. [Article:12861225], for both CYP2C9 in complex with warfarin and unliganded CYP2C9 (Protein Data Bank ID: 1OG2 and 1OG5, respectively). The structure showed unanticipated interactions between CYP2C9 and warfarin, revealing a new binding pocket, suggesting that CYP2C9 may simultaneously accommodate multiple ligands during its biologic function [Article:12861225]. Structural analysis suggested that CYP2C9 may undergo an allosteric change when binding warfarin [Article:12861225]. An X-ray crystal structure of CYP2C9, in complex with the NSAID flurbiprofen, has also been described (Protein Data Bank ID: 1R9O) [Article:15181000].

Genetic phenotypes and adverse drug reactions (ADR): The gene coding for the CYP2C9 enzyme is highly polymorphic, including functional variants of major pharmacogenetic importance. Changes in metabolic activity caused by genetic variants in CYP2C9 play a major role in pathogenesis due to ADRs. Patients with low enzyme activity are at risk of ADR, especially for CYP2C9 substrates with a narrow therapeutic window, such as S-warfarin, phenytoin, glipizide, and tolbutamide [Article:14511900]. A large body of literature investigates two common non-synonymous variants within CYP2C9 (R144C, [rs1799853] and I359L, [rs1057910]), leading to poor metabolism phenotypes. Both variants have significantly lower frequencies in African and Asian populations compared to Caucasian populations [Articles:11927841, 19151603], see frequency tables under Important variants. Individuals with these variants are at risk of prolonged bleeding time and increased incidence of severe bleeding in warfarin therapy [Article:10073515], higher possibility of low blood sugar levels during glipizide and tolbutamide therapy [Article:10208645], and more frequent symptoms of overdose in phenytoin therapy [Article:10774639]. Patients with the poor metabolizer *2 (identified by R144C) and *3 (identified by I359L) haplotypes require lower doses of warfarin to achieve a similar anticoagulant as patients with at least one *1 (wild-type) haplotype [Articles:10073515, 19031075]. However, it is now known that CYP2C9 genotype accounts for only part of the variability in warfarin sensitivity [Articles:11893129, 12621390] because VKORC1 genotype, age, and weight are also key factors in predicting the therapeutic dose for warfarin [Article:16424822]. CYP2C9 is responsible for about 90% of phenytoin metabolism, and the CYP2C9*2 and *3 haplotypes decrease the metabolism of phenytoin [Articles:19258521, 16873909, 11434505].

Besides the two variants mentioned above, a large number of SNPs have been described in the regulatory and coding regions of the CYP2C9 gene (http://www.cypalleles.ki.se/cyp2c9.htm). Some of the polymorphisms are associated with reduced enzyme activity compared to wild-type in in-vitro experiments; only a few enzyme experiments have been done in-vivo. CYP2C9*6 (818delA, rs933213) is a rare (1 allele in 158 African Americans, 0 in Caucasians) null allele with lack of activity due to a splicing mutation that causes a frameshift resulting in a truncated protein [Article:11740344]. The variant I359T (CYP2C*4) is also a rare (0.5% in African Americans, 6% in Caucasians) polymorphism [Articles:8873220, 9631918]. Both have been detected in patients who had adverse reactions to phenytoin [Articles:11740344, 10739176]. CYP2C9*5 (D360E, rs28371683), *6, *8 (R150H, rs7900194) and *11 (R335W, rs28371685) variants were associated with decreased phenytoin metabolism in a black population [Article:16220110]. The CYP2C9 promoter contains important regulatory elements: two HNF4 sites, a nuclear receptor pregnane X receptor binding site, a constitutive androstane receptor (CAR)/PXR site, and a glucocorticoid responsive element [Articles:15919766, 12181452, 11678789]. There have been multiple polymorphisms detected in the 5' untranslated region of CYP2C9 but these have not yet been shown to contribute to response to warfarin [Articles:15900281, 16513444] or phenytoin [Article:11434505] in-vivo, beyond those which appear to be in linkage disequilibrium with known exonic variants [Articles:15900281, 15070684, 11503012]. A recent paper investigating 22 known and 9 novel promoter SNPs with an in-vitro promoter activity assay suggests that genetic variation within CYP2C9 regulatory sequences is likely to contribute to differences in CYP2C9 phenotype, both within and among different populations, independent from known exonic variants [Article:18310303].