title: Mechanism-based inhibition of CYP450: an indicator of drug-induced hepatotoxicity.
abstract: Xenobiotics are converted by cytochrome P450 (CYP450) into highly reactive metabolites (RMs) that covalently bind to the catalytic site of the enzyme itself, subsequently causing mechanism-based inhibition. This phenomenon is one of the fates of RMs in the liver. Depending on their affinity to nucleophiles (high-electron density compounds), RMs also may act as hepatotoxic agents by binding to intracellular macromolecules. The present study summarized 29 mechanism-based inhibitors (drugs) with clinical hepatotoxicity. Eighteen of these drugs cause hepatotoxicity (7 through idiosyncratic drug-induced liver injury) via their RMs. The liver injury caused by remaining 11 drugs, namely, fluoxetine, verapamil, furan-containing compounds, and human immunodeficiency virus protease inhibitors, cannot be excluded via RMs because of limited data. A regular pattern for RM-induced hepatotoxicity is summarized: (a) formation of RM-protein adducts that trigger immune responses; (b) covalent binding of RMs to intracellular macromolecules (mitochondria is a commonly victim) may lead to reactive oxygen species (ROS) overproduction, respiratory chain dysfunction, cell stress, and so on; and (c) RM overproduction, which results in glutathione (GSH) depletion. The binding mechanism of RMs to CYP450s and the quantitative parameters (KI, Kinact, and Kinact/KI) of the mechanism-based inhibitors of CYP450s are weakly correlated with the occurrence of hepatotoxicity, while the induction of CYP450 expression (11/29 drugs) may contribute to hepatotoxicity via excessive ROS and RM generation. These results suggest that mechanism-based inhibition is an indicator of RM formation and may thus be used to identify drugs with RM-induced hepatotoxic potential (particularly idiosyncratic drug-induced liver injury).
authors.affiliation: School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Nankai District, Tianjin, P.R. China, 300193. hexintn@yahoo.com.
authors.forename: Shan
authors.initials: S
authors.lastname: Feng
authors.forename: Xin
authors.initials: X
authors.lastname: He
mesh_terms: D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System