These tools will no longer be maintained as of December 31, 2024. Archived website can be found here. PubMed4Hh GitHub repository can be found here. Contact NLM Customer Service if you have questions.


Pubmed for Handhelds

PUBMED FOR HANDHELDS

Search MEDLINE/PubMed

  • Title: Mechanism-based inhibition of CYP450: an indicator of drug-induced hepatotoxicity.
    Author: Feng S, He X.
    Journal: Curr Drug Metab; 2013 Nov; 14(9):921-45. PubMed ID: 24016115.
    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).
    [Abstract] [Full Text] [Related] [New Search]