Abstract

The effects of ethanol and acetaldehyde on the metabolism of leukotriene B₄ (LTB₄) and PGE₂ were investigated in isolated cultures of rat hepatocytes. LTB₄undergoes initial cytochrome P450-dependent ω-oxidation leading to the principal metabolites 20-hydroxy-LTB₄, 20-carboxy-LTB₄ and the ω/β-oxidation product 18-carboxy-LTB₄. The addition of low concentrations of ethanol (25 mM) dramatically changes the relative amounts of these metabolite products by inhibiting the alcohol dehydrogenase-mediated oxidation of 20-hydroxy-LTB₄. Addition of acetaldehyde to the incubation, up to 1 mM, had no significant effect on overall metabolism or distribution of metabolites. Above 1 mM acetaldehyde, β-oxidation of LTB₄ was inhibited. Thus the effect of ethanol on the metabolism of LTB₄ appears to be due to ethanol itself and not to secondary effects from the metabolic transformation of ethanol to acetaldehyde in the cells. PGE₂ is metabolized in isolated rat hepatocytes to produce chain-shortened products of β-oxidation characterized as dinor-PGE₁, dinor-PGE₂, tetranor-PGE₁, tauro-dinor-PGE₁ and tauro-dinor-PGE₂. Low concentrations of ethanol (25 mM) were found to increase the relative concentration of dinor-PGE₁ in the metabolic distribution, with a corresponding decrease in concentration of tetranor-PGE₁. The amount of dinor-PGE₂ that was produced remained relatively unchanged in response to increasing concentrations of ethanol. Acetaldehyde concentrations from 0.1 mM to 1 mM did not affect metabolite distribution or the overall magnitude of PGE₂metabolism. Concentrations of acetaldehyde higher than 1 mM decreased all β-oxidation metabolites. Ethanol, at physiologically relevant concentrations, could alter eicosanoid metabolism in the liver by inhibiting LTB₄ metabolism and altering that of PGE₂.