ω-Hydroxylation of farnesol by mammalian cytochromes P450

Studies have shown that mammalian cytochromes P450 participate in the metabolism of terpenes, yet their role in the biotransformation of famesol, an endogenous 15-carbon isoprenol, is unknown. In this report, [C-14] -famesol was transformed to more polar metabolites by NADPH-supplemented mammalian microsomes. In experiments with microsomes isolated from acetone-treated animals, the production of one polar metabolite was induced, suggesting catalysis by CYP2E1. The metabolite was identified as (2E, 6E, 10E)-12-hydroxyfamesol. In studies with purified CYP2E1, 12-hydroxyfamesol was obtained as the major product of famesol metabolism. Among a series of available human P450 enzymes, only CYP2C19 also produced 12-hydroxyfamesol. However, in individual human microsomes, CYP2E1 was calculated to contribute up to 62% toward total 12-hydroxyfamesol production, suggesting CYP2E1 as the major catalyst. Mammalian cells expressing CYP2E1 demonstrated further famesol metabolism to alpha.omega-prenyl dicarboxylic acids. Since such acids were identified in animal urine, the data suggest that CYP2E1 could be an important regulator of famesol homeostasis in vivo. In addition, CYP2E1-dependent 12-hydroxyfamesol formation was inhibited by pharmacological alcohol levels. Given that farnesol is a signaling molecule implicated in the regulation of tissue and cell processes, the biological activity of ethanol may be mediated in part by interaction with CYP2E1-dependent famesol metabolism. (C) 2004 Elsevier B.V All rights reserved.