Oxidative Drug Metabolism by Mammalian Cytochrome P450 Enzymes Using Their Monooxygenase and Peroxygenase Functions

Abstract The cytochrome P450 (CYP) enzyme system represents the predominant biotransformation pathway in the human body for lipophilic exogenous and endogenous compounds. The monooxygenase reaction catalyzed by CYP enzymes involves the addition of one oxygen atom from molecular oxygen to a lipophilic substrate, while incorporating the other oxygen atom into a molecule of water, thereby leading to the production of more polar and easily excreted metabolites. Thus, CYP enzymes are major determinants of duration of action and clearance of drugs. In some cases, CYP enzymes are involved in the formation of chemically reactive and potentially toxic metabolites, as well as in clinically significant drug–drug interactions, which are a widely recognized cause of adverse drug reactions in humans. This chapter focuses on the oxidative biotransformation of therapeutic drugs catalyzed by human CYP enzymes. The topics covered include the identification of human hepatic and extrahepatic CYP enzymes involved in drug biotransformation, CYP bioactivation of prodrugs to pharmacologically active compounds, human CYP drug–drug interactions, CYP monooxygenase and peroxygenase reactions involving drug substrates, and mechanisms involved in CYP oxidative drug reactions.