Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
Volume 1682, Issue 1-3, Pages 18-27Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbalip.2004.01.003
Keywords
(2E, 6E, 10E)-12-hydroxyfarnesol; CYP2E1; CYP2Cl9; alpha,omega-prenyl dicarboxylic acids; ethanol
Funding
- NIAAA NIH HHS [AA08608, AA13114] Funding Source: Medline
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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.
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