Ethanol-induced alteration of dopamine metabolism in rat liver

Abstract

Ethanol alters the metabolism of dopamine such that the final product is no longer predominantly the acid, 3,4-dihydroxyphenylacetic acid (DOPAC), but is a mixture of the acid and the alcohol derivative, 3,4-dihydroxyphenylethanol (DOPET). The ratio of DOPAC/DOPET produced in rat liver slices incubationed with [ethylamine-2- 14C]dopamine hydrochloride in the absence of ethanol is ca. 10, while in the presence of ethanol it is 0.25. Addition of alcohol dehydrogenase (ADH) inhibitors prevents the alteration in metabolism. Changing the NAD/NADH ratio of the liver cytosol by adding lactate to the incubation medium does not cause an alteration in the metabolism of dopamine. Acetaldehyde addition in the presence or absence of ADH inhibitors does not enhance the production of the alcohol derivative, though there was a small decrease in DOPAC levels. Thus, neither the decreased liver cytosol NAD/NADH ratio nor the preferential oxidation of acetaldehyde over 3,4-dihydroxyphenyl acetaldehyde (DOPAL) can explain the ethanol-induced alteration in dopamine metabolism. 3-Etiocholan-3β-o1-17-one, an alternative substrate for ADH, whose product of oxidation is neither a substrate nor an inhibitor of aldehyde dehydrogenase, mimics the effect of ethanol such that in its presence the metabolism of dopamine to its alcohol derivative is enhanced. An increased reduction of DOPAL by the NADPH-dependent aldehyde reductase cannot explain the dramatic enhancement of DOPET formation observed in the presence of ethanol or the sterol because the NADPH/ NADP ratio is normally very high in the liver. Due to the unique enzyme mechanism of ADH, in which the rate-limiting step of the reaction is the release of NADH from the enzyme, a finite concentration of the enzyme-NADH complex will exist during alcohol metabolism. We propose that the biogenic aldehyde binds to this form of ADH and is reduced.