Received for publication August 6, 2007.
Revised January 22, 2008.
Accepted for publication January 25, 2008.

Markers of Electrophilic Stress Caused by Chemically Reactive Metabolites in Human Hepatocytes

Abstract

The metabolic activation of a drug to an electrophilic reactive metabolite and its covalent binding to cellular macromolecules is considered to be involved in the occurrence of idiosyncratic drug toxicity. As a cellular defense system against oxidative and electrophilic stress, phase II enzymes are known to be induced through a Keap1/Nrf2/ARE system. We presumed that it is important for the risk assessment of drug-induced hepatotoxicity and IDTs to observe the biological responses evoked by exposure to reactive metabolites, and then investigated the mRNA induction profiles of phase II enzymes in human hepatocytes after exposure to problematic drugs associated with IDTs, such as ticlopidine, diclofenac, clozapine and tienilic acid, as well as safe drugs such as levofloxacin and caffeine. According to the results, the problematic drugs exhibited inductive effects on HO-1, which contrasted with the safe drugs, and therefore the induction of HO-1 mRNA seems to be correlated with the occurrence of drug toxicity including IDT due to electrophilic reactive metabolites. Moreover, GSH-depletion and CYP inhibition experiments have demonstrated that the observed HO-1 induction was triggered by the electrophilic reactive metabolites produced from the problematic drugs through CYP-mediated metabolic bioactivation. Taken together with our present study, this suggests that HO-1 induction in human hepatocytes would be a good marker of the occurrence of metabolism-based drug-induced hepatotoxicity and IDT due to the formation of electrophilic reactive metabolites.

Key words: drug-induced hepatotoxicity, glutathione conjugates, heme oxygenases, hepatocytes, idiosyncratic drug reactions, induction, oxidative stress, reactive intermediate, reactive metabolites

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