Cytochrome P450 1A2 (CYP1A2), Cytochrome P450 3A4 (CYP3A4), Cytochrome P450 2B6 (CYP2B6), Cytochrome P450 2C9 (CYP2C9), and Cytochrome P450 2D6 (CYP2D6) (CYP1A2/3A4/2B6/2C9/2D6)

The Cytochrome P450 (CYP) enzymes CYP1A2, CYP3A4, CYP2B6, CYP2C9, and CYP2D6 represent the primary enzymatic system responsible for the Phase I metabolism of the vast majority of clinical drugs (Zanger & Schwab, 2013). These heme-thiolate monooxygenases are predominantly expressed in the liver and catalyze the oxidation of lipophilic xenobiotics to facilitate their elimination from the body (Guengerich, 2008). CYP3A4 is the most abundant isoform, involved in the metabolism of approximately 50% of marketed drugs, while CYP2D6 and CYP2C9 are highly polymorphic, leading to significant inter-individual variability in drug response and safety (FDA, 2020). Although these enzymes are rarely the intended therapeutic targets for disease modification, they are critical in drug development because their inhibition or induction can lead to dangerous drug-drug interactions (Lynch & Price, 2007). For instance, inhibition of CYP3A4 by ketoconazole can lead to toxic levels of co-administered substrates, while genetic deficiencies in CYP2D6 can render prodrugs like codeine ineffective (StatPearls, 2023). Consequently, characterizing the interaction of any new molecular entity with these five specific isoforms is a mandatory component of regulatory safety assessments (FDA, 2020).

Other names

Cytochrome P450 superfamilyPhase I drug metabolism enzymesMicrosomal monooxygenase systemHeme-thiolate monooxygenases

Substrate oxidation and biotransformation; enzymatic inhibition or induction by various pharmacological agents.