Enhancement of Quinone Hepatotoxicity by Cytochrome P450 Inhibition

Abstract

Quinones are widely distributed in nature, and some quinone compounds are used as therapeutic agents such as anti-cancer, anti-malarial or anti-bacterial drugs. However, their therapeutic use is limited in some cases because the use of most quinones is accompanied by adverse effects derived from their cytotoxicity, especially for hepatocytes. Two mechanisms have been proposed to explain quinone toxicity: oxidative stress via redox cycle and the arylation/alkylation of intracellular nucleophiles. A drug metabolizing enzyme, cytochrome P450 is closely involved in the hepatotoxicity of therapeutic agents in general, but quinone hepatotoxicity has been considered not to contribute to cytochrome P450 because the structure of quinone is not modified by cytochrome P450 and thus quinone compounds are thought to be metabolized mainly via a conjugation process. However, we have recently shown that quinone hepatotoxicity is enhanced under conditions of cytochrome P450 inhibition, indicating clearly the involvement of cytochrome P450 in quinone hepatotoxicity. Here, we revisit the generally accepted mechanisms of quinone hepatotoxicity and propose the importance of cytochrome P450 systems in quinone-induced hepatotoxicity on the basis of our recent work.