CYP2C9

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.^[5][6] The gene is highly polymorphic, which affects the efficiency of the metabolism by the enzyme.^[7]

Function

CYP2C9 is a crucial

The label CYP2C9*1 is assigned by the Pharmacogene Variation Consortium (PharmVar) to the most commonly observed human gene variant.^[21] Other relevant variants are cataloged by PharmVar under consecutive numbers, which are written after an asterisk (star) character to form an allele label.^[22][23] 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),^[24] causing reductions in enzyme activity of 30% and 80%, respectively.^[16]

Metabolizer phenotypes

On the basis of their ability to metabolize CYP2C9 substrates, individuals can be categorized by groups. The carriers of homozygous CYP2C9*1 variant, i.e. of the *1/*1 genotype, are designated extensive metabolizers (EM), or normal metabolizers.^[25] 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).^[26][27] 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.^[28]

CYP2C9*3 reflects an Ile359-Leu (I359L) change in the amino acid sequence,^[29] and also has reduced catalytic activity compared with the wild type (CYP2C9*1) for substrates other than warfarin.^[30] Its prevalence varies with race as:

Test panels of variant alleles

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.^[16]

CYP2C9*13 is defined by a missense variant in exon 2 (NM_000771.3:c.269T>C, p. Leu90Pro, rs72558187).^[16] CYP2C9*13 prevalence is approximately 1% in the Asian population,^[31] but in Caucasians this variant prevalence is almost zero.^[32] 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.^[31] However, this variant is not included in the tier 1 recommendations of the PGx Working Group because of its very low multiethnic minor allele frequency and a lack of currently available reference materials.^[16] As of 2020^[update] the evidence level for CYP2C9*13 in the PharmVar database is limited, comparing to the tier 1 alleles, for which the evidence level is definitive.^[21]

Additional variants

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.^[33] 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.^[34] 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.^[35] 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.^[36] 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.^[37][38]

Ligands

Most inhibitors of CYP2C9 are

Inhibitors of CYP2C9 can be classified by their potency, such as:

• Strong being one that causes at least a 5-fold increase in the plasma
  clearance.^[44]
• Moderate being one that causes at least a 2-fold increase in the plasma AUC values, or a 50–80% decrease in clearance.[44]
• Weak being one that causes at least a 1.25-fold but less than 2-fold increase in the plasma AUC values, or 20–50% decrease in clearance.^[44][45]

Epoxygenase activity

CYP2C9 attacks various long-chain polyunsaturated fatty acids at their double (i.e.

Further reading

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• Goldstein JA, de Morais SM (December 1994). "Biochemistry and molecular biology of the human CYP2C subfamily". Pharmacogenetics. 4 (6): 285–299.
  PMID 7704034
  .
• Miners JO, Birkett DJ (June 1998). "Cytochrome P4502C9: an enzyme of major importance in human drug metabolism". British Journal of Clinical Pharmacology. 45 (6): 525–538.
  PMID 9663807
  .
• Smith G, Stubbins MJ, Harries LW, Wolf CR (December 1998). "Molecular genetics of the human cytochrome P450 monooxygenase superfamily". Xenobiotica. 28 (12): 1129–1165.
  PMID 9890157
  .
• Henderson RF (June 2001). "Species differences in the metabolism of olefins: implications for risk assessment". Chemico-Biological Interactions. 135–136: 53–64.
  PMID 11397381
  .
• Xie HG, Prasad HC, Kim RB, Stein CM (November 2002). "CYP2C9 allelic variants: ethnic distribution and functional significance". Advanced Drug Delivery Reviews. 54 (10): 1257–1270.
  PMID 12406644
  .
• Palkimas MP, Skinner HM, Gandhi PJ, Gardner AJ (June 2003). "Polymorphism induced sensitivity to warfarin: a review of the literature". Journal of Thrombosis and Thrombolysis. 15 (3): 205–212.
  S2CID 20497247
  .
• Daly AK, Aithal GP (August 2003). "Genetic regulation of warfarin metabolism and response". Seminars in Vascular Medicine. 03 (3): 231–238.
  S2CID 260370436
  .

External links

Wikimedia Commons has media related to CYP2C9.

• PharmGKB: Annotated PGx Gene Information for CYP2C9
• SuperCYP: Database for Drug-Cytochrome-Interactions Archived 3 November 2011 at the Wayback Machine
• PharmVar Database for CYP2C9
• Human CYP2C9 genome location and CYP2C9 gene details page in the UCSC Genome Browser.