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).

Antifungal Activity of the Lipophilic Antioxidant Ferrostatin‐1

“…In the setting of ferroptosis, oxidation‐activated Fer‐1 could also react with lipid aldehydes or Acyl‐CoA lipid intermediates. In the antifungal interaction with CYP51, Fer‐1 might react irreversibly with either the heme group or the protein, a known form of CYP450‐family enzyme inactivation . Conversely, the benzimidazole and benzotriazole analogues of Fer‐1 (FA‐3 and FA‐4) are expected to interact with CYP51 reversibly; this could account for their lower antifungal potency.…”

Mechanism-based inhibition of CYPs and RMs-induced hepatoxicity by rutaecarpine

“…Therefore, MBI on CYPs was an indicator for RMs formation and for identifying candidate compounds with potential RMs-induced hepatotoxicity. Previous studies have reported that chemicals with secondary amine structure would generate RMs in metabolism and cause a drug-induced liver injury (Feng & He, 2013). The structure-related compounds would be also useful to obtain the information of structurerelationship with toxicity.…”

Time-dependent inhibition of CYP3A4 by gallic acid in human liver microsomes and recombinant systems

“…However, gallic acid is not a mechanism-based inactivator of CYP3A4, since the features of concentration-, time-and NADPH-dependence that define mechanism-based inactivation were incompletely met by the gallic acid inactivation of CYP3A4 (Feng & He 2013;Kamel & Harriman 2013;Zhou et al, 2005). For example, inactivation by gallic acid is not characterized by NADPH dependence.…”