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).
Keywords: Mechanism-based inhibition, reactive metabolites, hepatotoxicity, CYP450, immune response, GSH depletion, CYP450 RNA or
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