Target intelligence / Profile preview

Cytochrome P450 family 2 subfamily C member 8, Cytochrome P450 family 2 subfamily C member 9, and Cytochrome P450 family 2 subfamily C member 19 (CYP2C8, CYP2C9, CYP2C19)

Target
CYP2C8, CYP2C9, CYP2C19
Molecular classification
Enzyme, Oxidoreductase, Cytochrome P450 family member
01

Overview

CYP2C8, CYP2C9, and CYP2C19 are closely related but distinct enzymes of the cytochrome P450 superfamily, encoded by separate genes located together on chromosome 10. These hepatic microsomal enzymes are responsible for the oxidative metabolism of a broad range of clinically important drugs and endogenous compounds, accounting for about 20-25% of all cytochrome P450 content in the adult human liver. Each enzyme displays substrate specificity but with some overlap, particularly in the metabolism of nonsteroidal anti-inflammatory drugs, oral hypoglycemics, and chemotherapeutics. All three have highly polymorphic genes, making pharmacogenomic profiling relevant for predicting drug efficacy and risk of adverse effects. Inhibition, induction, or genetic variation in these enzymes is a major source of variability in drug responses and a common mechanism for drug-drug interactions in the clinic.

Other names
Cytochrome P450 2C8Cytochrome P450 2C9Cytochrome P450 2C19(R)-limonene 6-monooxygenase(S)-limonene 6-monooxygenaseCYP2C subfamily
02

Mechanism of action

Substrate oxidation (phase I metabolism): drugs are hydroxylated, demethylated, or otherwise oxidized Prodrug activation (e.g., clopidogrel by CYP2C19) Drug inactivation leading to decreased efficacy (e.g., proton pump inhibitors by CYP2C19) Generation of pharmacologically active or toxic metabolites

03

Biological functions

Drug metabolismMetabolism of endogenous compounds (e.g., arachidonic acid, steroids, fatty acids)Biosynthesis of cholesterol, steroids, and other lipids
04

Disease associations

Adverse drug reactions (due to genetic polymorphisms affecting enzyme activity)Variable drug efficacy and risk of toxicity ("pharmacogenomics relevant" drug targets)Cardiovascular disease (e.g., through metabolism of antiplatelet drugs like clopidogrel, metabolism of arachidonic acid to vasoactive EETs)Cancer, due to involvement in oxidation of chemotherapeutics (e.g., paclitaxel)Other, depending on drug substrate
05

Safety considerations

Risk of adverse drug reactions/toxicity from poor or ultra-rapid metabolismSignificant drug-drug interactions via inhibition or induction of these enzymesNarrow therapeutic index drugs especially vulnerable (e.g., warfarin, phenytoin)Genetic polymorphisms can render some drugs ineffective or toxic at standard doses
06

Interacting drugs

paclitaxel

22 more in the full profile.

07

Biomarkers

Genetic variants (SNPs/haplotypes in CYP2C8, CYP2C9, CYP2C19 impacting drug metabolism phenotypes)Metabolic ratios for probe drugs (e.g., S-warfarin 7-hydroxylation for CYP2C9 activity, mephenytoin 4'-hydroxylation for CYP2C19)

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