CYP2C9
Cytochrome P450 2C9 is an enzyme that in humans is encoded by the CYP2C9 gene.
Function
CYP2C9 is an important cytochrome P450 enzyme with a major role in the oxidation of both xenobiotic and endogenous compounds. CYP2C9 makes up about 18% of the cytochrome P450 protein in liver microsomes. Some 100 therapeutic drugs are metabolized by CYP2C9, including drugs with a narrow therapeutic index such as warfarin and phenytoin, and other routinely prescribed drugs such as acenocoumarol, tolbutamide, losartan, glipizide, and some nonsteroidal anti-inflammatory drugs. By contrast, the known extrahepatic CYP2C9 often metabolizes important endogenous compounds such as serotonin and, owing to its epoxygenase activity, various polyunsaturated fatty acids, converting these fatty acids to a wide range of biological active products.In particular, CYP2C9 metabolizes arachidonic acid to the following eicosatrienoic acid epoxide stereoisomer sets: 5R,6S-epoxy-8Z,11Z,14Z-eicosatetrienoic and 5S,6R-epoxy-8Z,11Z,14Z-eicosatetrienoic acids; 11R,12S-epoxy-8Z,11Z,14Z-eicosatetrienoic and 11S,12R-epoxy-5Z,8Z,14Z-eicosatetrienoic acids; and 14R,15S-epoxy-5Z,8Z,11Z-eicosatetrainoic and 14S,15R-epoxy-5Z,8Z,11Z-eicosatetrainoic acids. It likewise metablizes docosahexaenoic acid to epoxydocosapentaenoic acids and eicosapentaenoic acid to epoxyeicosatetraenoic acids. 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.
In vitro studies on human and animal cells and tissues and in vivo animal model studies indicate that certain EDPs and EEQs have actions which often oppose those of another product of CYP450 enzymes viz., 20-Hydroxyeicosatetraenoic acid, principally in the areas of blood pressure regulation, blood vessel thrombosis, and cancer growth more potent than EETs in decreasing hypertension and pain perception; 2) more potent than or equal in potency to the EETs in suppressing inflammation; and 3)''' act oppositely from the EETs in that they inhibit angiogenesis, endothelial cell migration, endothelial cell proliferation, and the growth and metastasis of human breast and prostate cancer cell lines whereas EETs have stimulatory effects in each of these systems. 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 and coronaric acid ; these linoleic acid epoxides cause multiple organ failure and acute respiratory distress in animal models and may contribute to these syndromes in humans.
Pharmacogenomics
exists for CYP2C9 expression because the CYP2C9 gene is highly polymorphic. More than 50 single nucleotide polymorphisms have been described in the regulatory and coding regions of the CYP2C9 gene; some of them are associated with altered enzyme activity compared with wild type.Multiple in vivo studies also show that several mutant CYP2C9 genotypes are associated with significant reduction of in metabolism and daily dose requirements of selected CYP2C9 substrate. In fact, adverse drug reactions 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.
The Pharmacogene Variation Consortium keeps the and assigns labels to known polymorphysms. The label CYP2C9*1 is assigned to normal enzyme function. The two most well-characterized variant alleles are CYP2C9*2 and CYP2C9*3, causing reductions in enzyme activity of 30% and 80%, respectively.
On the basis of their ability to metabolize CYP2C9 susbstrates, individuals can be categorized by groups. The carriers of homozygote CYP2C9*1, i.e. of the *1/*1 genotype, are designated extensive metabolizers. The carriers of the CYP2C9*2 and CYP2C9*3 alleles in a heterozygous state are designated intermediate metabolizers, and those carrying two of these alleles — poor metabolizers.
A study of the ability to metabolize warfarin among the carriers of the most well-caracterized CYP2C9 genotypes, expressed as percentage of the mean dose in patients with wild-type alleles, 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.
Allele frequencies of CYP2C9 polymorphism
| African-American | Black-African | Pygmy | Asian | Caucasian | |
| CYP2C9*2 | 2.9 | 0-4.3 | 0 | 0-0.1 | 8-19 |
| CYP2C9*3 | 2.0 | 0-2.3 | 0 | 1.1-3.6 | 3.3-16.2 |
| CYP2C9*5 | 0-1.7 | 0.8-1.8 | ND | 0 | 0 |
| CYP2C9*6 | 0.6 | 2.7 | ND | 0 | 0 |
| CYP2C9*7 | 0 | 0 | 6 | 0 | 0 |
| CYP2C9*8 | 1.9 | 8.6 | 4 | 0 | 0 |
| CYP2C9*9 | 13 | 15.7 | 22 | 0 | 0.3 |
| CYP2C9*11 | 1.4-1.8 | 2.7 | 6 | 0 | 0.4-1.0 |
| CYP2C9*13 | ND | ND | ND | 0.19-0.45 | ND |
CYP2C9 Ligands
Most inhibitors of CYP2C9 are competitive inhibitors. Noncompetitive inhibitors of CYP2C9 include nifedipine, phenethyl isothiocyanate, medroxyprogesterone acetate and 6-hydroxyflavone. It was indicated that the noncompetitive binding site of 6-hydroxyflavone is the reported allosteric binding site of the CYP2C9 enzyme.Following is a table of selected substrates, inducers and inhibitors of CYP2C9. Where classes of agents are listed, there may be exceptions within the class.
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 AUC values, or more than 80% decrease in clearance.
- Moderate being one that causes at least a 2-fold increase in the plasma AUC values, or 50-80% decrease in clearance.
- 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.
| Substrates | Inhibitors | Inducers |
| Strong Moderate Unspecified potency
| Strong Weak |