Cytochrome P450 3A4 and Cytochrome P450 2A6 (CYP3A4 and CYP2A6)

Cytochrome P450 3A4 (CYP3A4) and Cytochrome P450 2A6 (CYP2A6) are essential heme-thiolate monooxygenases involved in the phase I metabolism of drugs and endogenous compounds (UniProt: P08684, P11509). CYP3A4 is the most prevalent P450 enzyme in the human liver and small intestine, facilitating the metabolism of over 50% of marketed drugs, including macrolides, benzodiazepines, and statins (NCBI: Gene ID 1576). CYP2A6 is primarily responsible for the metabolism of nicotine and the activation of several tobacco-related procarcinogens (NCBI: Gene ID 1548). Rodent CYP2A3 is the functional ortholog of human CYP2A6, often utilized in toxicological studies to model human metabolic pathways (PubMed: 15505164). These enzymes play a pivotal role in determining drug bioavailability and are major drivers of clinically significant drug-drug interactions (PubMed: 11470988). Their activity is highly variable among individuals due to both genetic polymorphisms and environmental induction or inhibition, which can lead to therapeutic failure or adverse drug reactions (StatPearls: NBK557498). Inhibition of CYP3A4 by drugs like ketoconazole can lead to toxic levels of co-administered medications, while induction by rifampicin can reduce efficacy. Similarly, CYP2A6 genetic variants significantly influence smoking behavior and the risk of tobacco-related cancers.

Other names

CYP3A4CYP2A6CYP2A3Nifedipine oxidaseCoumarin 7-hydroxylase1,4-cineole 2-exo-monooxygenaseCYP3A3CYP2A

Oxidative metabolism of substrates via the insertion of one atom of oxygen into the substrate molecule, facilitated by the heme-iron center and electron transfer from NADPH-cytochrome P450 reductase (PubMed: 11470988).