ω-Hydroxylation of farnesol by mammalian cytochromes P450

Andrea E. DeBarber, Lisa A. Bleyle, Jean Baptiste O. Roullet, Dennis R. Koop

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Studies have shown that mammalian cytochromes P450 participate in the metabolism of terpenes, yet their role in the biotransformation of farnesol, an endogenous 15-carbon isoprenol, is unknown. In this report, [ 14C]-farnesol 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-hydroxyfarnesol. In studies with purified CYP2E1, 12-hydroxyfarnesol was obtained as the major product of farnesol metabolism. Among a series of available human P450 enzymes, only CYP2C19 also produced 12-hydroxyfarnesol. However, in individual human microsomes, CYP2E1 was calculated to contribute up to 62% toward total 12-hydroxyfarnesol production, suggesting CYP2E1 as the major catalyst. Mammalian cells expressing CYP2E1 demonstrated further farnesol metabolism to α,ω-prenyl dicarboxylic acids. Since such acids were identified in animal urine, the data suggest that CYP2E1 could be an important regulator of farnesol homeostasis in vivo. In addition, CYP2E1-dependent 12-hydroxyfarnesol 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 farnesol metabolism.

Original languageEnglish (US)
Pages (from-to)18-27
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volume1682
Issue number1-3
DOIs
StatePublished - Jun 1 2004

Keywords

  • (2E, 6E, 10E)-12-hydroxyfarnesol
  • CID
  • CYP2C19
  • CYP2E1
  • Ethanol
  • FPP
  • LPDS
  • TLC
  • ZA
  • collision-induced dissociation
  • farnesyl pyrophosphate
  • lipoprotein-deficient serum
  • thin-layer chromatography
  • zaragozic acid
  • α,ω-prenyl dicarboxylic acids

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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