TY - JOUR
T1 - ω-Hydroxylation of farnesol by mammalian cytochromes P450
AU - DeBarber, Andrea E.
AU - Bleyle, Lisa A.
AU - Roullet, Jean Baptiste O.
AU - Koop, Dennis R.
N1 - Funding Information:
We would like to thank Dr. Jim R. Halpert for the CYP2E1dH plasmid and Patrick G. MacDougal for all-trans farnesoic acid. This work was supported by NIAAA grants AA08608 and AA13114.
PY - 2004/6/1
Y1 - 2004/6/1
N2 - 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.
AB - 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.
KW - (2E, 6E, 10E)-12-hydroxyfarnesol
KW - CID
KW - CYP2C19
KW - CYP2E1
KW - Ethanol
KW - FPP
KW - LPDS
KW - TLC
KW - ZA
KW - collision-induced dissociation
KW - farnesyl pyrophosphate
KW - lipoprotein-deficient serum
KW - thin-layer chromatography
KW - zaragozic acid
KW - α,ω-prenyl dicarboxylic acids
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U2 - 10.1016/j.bbalip.2004.01.003
DO - 10.1016/j.bbalip.2004.01.003
M3 - Article
C2 - 15158752
AN - SCOPUS:2442688821
SN - 1388-1981
VL - 1682
SP - 18
EP - 27
JO - Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
JF - Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
IS - 1-3
ER -