Genetically Determined Response of Hepatic Aldehyde Dehydrogenase Activity to Ethanol Exposures May Be Associated with Alcohol Sensitivity in Mouse Genotypes

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Abstract
Mice (Mus musculus) from four genetic strains (BALB/c, C57BL/6J, 12Q/ReJ, and SW) and their F, hybrids (SWxBALB/c, C57BL/6JWxBALB/c, and C57BL/6Jx129/ReJ) were used to evaluate the effect of ethanol on the activity of the two primary enzymes, alcohol dehydrogenase (ADH; E.C.1.1.1.1) and aldehyde dehydrogenase (ALDH; E.C. 1.2.1.3), of alcohol metabolism. Three week‐old male mice (12–16 g) were placed on liquid diet (5% ethanol) while a weight‐matched littermate control was fed isocaloric maltose‐dextrin in place of ethanol. Animals were sacrificed after 3 weeks and the liver and stomach were excised for biochemical analysis. Although the ethanol feeding did not influence the stomach ADH and ALDH activity levels, these enzymes in the liver were affected. The liver ADH activity was depressed to varying degrees in all mouse genotypes studied. Also, the ethanol feeding altered the liver‐ALDH activity, which was highly variable and genotype specific. The mice of C57BL/6J and F, C57BL/GJxBALB/c, both relatively resistant genotypes, exhibited significant increase in liver ALDH‐(cytosolic and whole liver homogenate) activity. The response in the other genotypes were not significantly different from their matched controls. The relative resistance of the C57BL/6J strain may be associated with the increase in liver ALDH activity which is expected to facilitate the elimination of acteladehyde, the toxic metabolite. The results from the selected F1 crosses indicate a multigene system regulating the inducibility of the liver ALDH. The relative sensitivity of different genotypes may be attributed to inducibility components regulating the liver enzyme activity, particularty liver ALDH following challenges with ethanol. These observations may offer a new approach in explaining extensive variability in response to alcohols in most populations.