The effects of ethanol and acetaldehyde on the metabolism of prostaglandin E2 and leukotriene B4 in isolated rat hepatocytes.
The effects of ethanol and acetaldehyde on the metabolism of leukotriene B4 (LTB4) and PGE2 were investigated in isolated cultures of rat hepatocytes. LTB4 undergoes initial cytochrome P450-dependent omega-oxidation leading to the principal metabolites 20-hydroxy-LTB4, 20-carboxy-LTB4 and the omega/beta-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, beta-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 beta-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 PGE2 metabolism. Concentrations of acetaldehyde higher than 1 mM decreased all beta-oxidation metabolites. Ethanol, at physiologically relevant concentrations, could alter eicosanoid metabolism in the liver by inhibiting LTB4 metabolism and altering that of PGE2.
Hankin
J A
JA
Department of Pediatrics, Division of Basic Sciences, National Jewish Medical and Research Center, Denver, Colorado 80206, USA.
Clay
C E
CE
Murphy
R C
RC
D000079:Acetaldehyde / Q000494:pharmacology*; D000818:Animals; D018929:Cell Culture Techniques; D002851:Chromatography, High Pressure Liquid; D015232:Dinoprostone / Q000378:metabolism*; D000431:Ethanol / Q000494:pharmacology*; D007975:Leukotriene B4 / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051381:Rats
D007975:Leukotriene B4; D000431:Ethanol; D000079:Acetaldehyde; D015232:Dinoprostone