Ethanol (alcohol) is converted into acetyl CoA by mammalian cells and serves as metabolic precursor to the synthesis of mevalonate and mevalonate-derived endogenous farnesol, a 15-carbon long isoprenol. In the liver, the enzymes which oxidize ethanol also control the oxidation of farnesol into farnesal and farnesoic acid. Several studies including studies by our group indicate that farnesol is implicated in cell growth, apoptosis, nuclear receptor activation, voltage-gated Ca2+ channel activity and free radical production. Because ethanol also affects these processes, and because both alcohols share common metabolic pathways, it is possible that the adverse effects of ethanol and alcoholism in general, are in part, secondary to the metabolic interaction of ethanol with the farnesol pathway. To support this hypothesis, we propose to collect preliminary data providing evidence that indeed ethanol modifies farnesol metabolism. Our objectives are: 1. To determine if ethanol affects the in vivo metabolism of radioactive MVA into hepatic farnesoids, 2. To determine if ethanol administration affects hepatic farnesol concentrations, and To characterize the effect of acute and chronic ethanol on farnesol metabolism by subcellular fractions. Experiments will be performed in the C57BL/6J mouse strain. The data will be used as a foundation to future projects addressing the issues of ethanol/farnesol metabolic interactions in other tissues and evaluating the contribution of farnesol to ethanol toxicity in target tissues. Finally, the data will serve as a rationale to characterize farnesol metabolism in alcohol-sensitive individuals or animals or to examine new pharmacological strategies for the treatment of alcohol toxicity based on modulation of the farnesol pathway.
|DeBarber, Andrea E; Bleyle, Lisa A; Roullet, Jean-Baptiste O et al. (2004) Omega-hydroxylation of farnesol by mammalian cytochromes p450. Biochim Biophys Acta 1682:18-27|