SUBSTRATES OF HUMAN HEPATIC CYTOCHROME-P450 3A4

Cytochrome P450 isozyme 3A4 (CYP3A4) is a major isozyme in the human l iver and is known to metabolize a large variety of xenobiotics and end ogenous biochemicals. The identities of CYP3A4 substrates are summariz ed here. A total of 32 chemicals belonging to different structural cla sses have been evaluated and found to be substrates for CYP3A4. The me tabolic pathways for these substrates include N-oxidation, C-oxidation , N-dealkylation, O-dealkylation, nitroreduction, dehydration, and C-h ydroxylation, While the major experimental system used to elucidate th e role of CYP3A4 in the metabolic transformation of these substrates i s the human liver microsome system, cultured human hepatocytes and yea st/cultured cells genetically engineered to express CYP3A4 are also em ployed by the different investigators. The common approaches to identi fy the role of CYP3A4 are also summarized, which include correlation o f metabolic activity of the substrates studied with those for known CY P3A4-catalyzed substrates, correlation of activity with CYP3A4 content , inhibition of activity with CYP3A4 specific antibodies, inhibition o f activity with known CYP3A4 substrates and inhibitors, induction of a ctivity with CYP3A4 inducers and demonstration of activity with purifi ed CYP3A4 enzyme.