CYP2C9

Enzyme protein

Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in the metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the protein is encoded by the CYP2C9 gene. The gene is highly polymorphic, which affects the efficiency of the metabolism by the enzyme.

CYP2C9 is a crucial cytochrome P450 enzyme, which plays a significant role in the metabolism, by oxidation, of both xenobiotic and endogenous compounds. Animal models and a limited number of human studies implicate these epoxides in reducing hypertension; protecting against myocardial infarction and other insults to the heart; promoting the growth and metastasis of certain cancers; inhibiting inflammation; stimulating blood vessel formation; and possessing a variety of actions on neural tissues including modulating neurohormone release and blocking pain perception (see epoxyeicosatrienoic acid and epoxygenase). Consumption of omega 3 fatty acid rich diets dramatically raises the serum and tissue levels of EDPs and EEQs in animals as well as humans, and in humans is by far the most prominent change in the profile of polyunsaturated fatty acids metabolites caused by dietary omega 3 fatty acids. CYP2C9 may also metabolize linoleic acid to the potentially very toxic products, vernolic acid (also termed leukotoxin) and coronaric acid (also termed isoleukotoxin); these linoleic acid epoxides cause multiple organ failure and acute respiratory distress in animal models and may contribute to these syndromes in humans. In fact, adverse drug reactions (ADRs) often result from unanticipated changes in CYP2C9 enzyme activity secondary to genetic polymorphisms. Especially for CYP2C9 substrates such as warfarin and phenytoin, diminished metabolic capacity because of genetic polymorphisms or drug drug interactions can lead to toxicity at normal therapeutic doses. Information about how human genetic variation of CYP2C9 affects response to medications can be found in databases such PharmGKB, Clinical Pharmacogenetics Implementation Consortium (CPIC). The label CYP2C9*1 is assigned by the Pharmacogene Variation Consortium (PharmVar) to the most commonly observed human gene variant. The two most well characterized variant alleles are CYP2C9*2 (NM 000771.3:c.430C>T, p. Arg144Cys, rs1799853) and CYP2C9*3 (NM 000771.3:c.1075A>C, p. Ile359Leu, rs1057910), causing reductions in enzyme activity of 30% and 80%, respectively. The carriers of the CYP2C9*2 or CYP2C9*3 alleles in a heterozygous state, i. e. just one of these alleles (*1/*2, *1/*3) are designated intermediate metabolizers (IM), and those carrying two of these alleles, i. e. homozygous (*2/*3, *2/*2 or *3/*3) – poor metabolizers (PM). As a result, the metabolic ratio – the ratio of unchanged drug to metabolite – is higher in PMs. A study of the ability to metabolize warfarin among the carriers of the most well characterized CYP2C9 genotypes (*1, *2 and *3), expressed as a percentage of the mean dose in patients with wild type alleles (*1/*1), concluded that the mean warfarin maintenance dose was 92% in *1/*2, 74% in *1/*3, 63% in *2/*3, 61% in *2/*2 and 34% in 3/*3. CYP2C9*3 reflects an Ile359 Leu (I359L) change in the amino acid sequence, and also has reduced catalytic activity compared with the wild type (CYP2C9*1) for substrates other than warfarin. Its prevalence varies with race as:

Allele frequencies (%) of CYP2C9 polymorphism African American Black African Pygmy Asian Caucasian CYP2C9*3 2.0 0–2.3 0 1.1–3.6 3.3–16.2

The Association for Molecular Pathology Pharmacogenomics (PGx) Working Group in 2019 has recommended a minimum panel of variant alleles (Tier 1) and an extended panel of variant alleles (Tier 2) to be included in assays for CYP2C9 testing. CYP2C9 variant alleles recommended as Tier 1 by the PGx Working Group include CYP2C9 *2, *3, *5, *6, *8, and *11. This recommendation was based on their well established functional effects on CYP2C9 activity and drug response availability of reference materials, and their appreciable allele frequencies in major ethnic groups. The following CYP2C9 alleles are recommended for inclusion in tier 2: CYP2C9*12, *13, and *15. but in Caucasians this variant prevalence is almost zero. This variant is caused by a T269C mutation in the CYP2C9 gene which in turn results in the substitution of leucine at position 90 with proline (L90P) at the product enzyme protein. This residue is near the access point for substrates and the L90P mutation causes lower affinity and hence slower metabolism of several drugs that are metabolized CYP2C9 by such as diclofenac and flurbiprofen.

Not all clinically significant genetic variant alleles have been registered by PharmVar. For example, in a 2017 study, the variant rs2860905 showed stronger association with warfarin sensitivity (<4 mg/day) than common variants CYP2C9*2 and CYP2C9*3. Allele A (23% global frequency) is associated with a decreased dose of warfarin as compared to the allele G (77% global frequency). Another variant, rs4917639, according to a 2009 study, has a strong effect on warfarin sensitivity, almost the same as if CYP2C9*2 and CYP2C9*3 were combined into a single allele. The C allele at rs4917639 has 19% global frequency. Patients with the CC or CA genotype may require decreased dose of warfarin as compared to patients with the wild type AA genotype. Another variant, rs7089580 with T allele having 14% global frequency, is associated with increased CYP2C9 gene expression. Carriers of AT and TT genotypes at rs7089580 had increased CYP2C9 expression levels compared to wild type AA genotype. Increased gene expression due to rs7089580 T allele leads to an increased rate of warfarin metabolism and increased warfarin dose requirements. In a study published in 2014, the AT genotype showed slightly higher expression than TT, but both much higher than AA. Another variant, rs1934969 (in studies of 2012 and 2014) have been shown to affect the ability to metabolize losartan: carriers of the TT genotype have increased CYP2C9 hydroxylation capacity for losartan comparing to AA genotype, and, as a result, the lower metabolic ratio of losartan, i. e., faster losartan metabolism.