Cytochrome P450 family 3 subfamily A member 4 (CYP3A4) and Cytochrome P450 family 2 subfamily D member 6 (CYP2D6) (CYP3A4 and CYP2D6)

Cytochrome P450 3A4 (CYP3A4) and Cytochrome P450 2D6 (CYP2D6) are the two most clinically relevant enzymes of the cytochrome P450 (CYP) superfamily, collectively responsible for the metabolism of over 70% of marketed drugs (NIH, 2023). CYP3A4 is the most abundant CYP enzyme in the human liver and small intestine, exhibiting broad substrate specificity for drugs such as statins, calcium channel blockers, and benzodiazepines (UniProt P08684). In contrast, CYP2D6 is highly polymorphic, with over 100 known allelic variants that categorize individuals into poor, intermediate, extensive, or ultra-rapid metabolizers, significantly impacting the efficacy and safety of drugs like tamoxifen and codeine (PharmGKB, 2022). While these enzymes are not typically primary therapeutic targets for disease modification, they are critical considerations in drug development due to their role in drug-drug interactions (DDIs) and pharmacogenomics (FDA, 2020). Inhibition or induction of these enzymes can lead to profound changes in drug exposure, potentially causing life-threatening toxicity or loss of therapeutic effect (PubMed PMC3918163). Consequently, screening for CYP3A4 and CYP2D6 interaction is a regulatory requirement in the development of nearly all small-molecule therapeutics. These enzymes also play roles in the metabolism of endogenous compounds such as steroids and fatty acids, though their xenobiotic function is of primary clinical interest (UniProt P10635).

Other names

Cytochrome P450 3A4Cytochrome P450 2D6Nifedipine oxidaseDebrisoquine 4-hydroxylaseCYP3ACYP2D

Metabolic oxidation of substrates; competitive or non-competitive inhibition; transcriptional induction.