The long-term objective is to enhance our understanding of mechanisms responsible for individual variation in rate of ethanol metabolism. This proposal focuses on the major enzyme of alcohol metabolism, alcohol dehydrogenase (ADH), and takes advantage of the baboon as a unique primate model in which influences of genetic variation and of alcohol consumption on alcohol elimination rates can be investigated.
The specific aims are 1) to determine if deficiency of the liver class II ADH isozyme (ADH-4), which is present in some baboons but not others, is associated with reduced rate of alcohol clearance; 2) to determine the effect of moderate and moderately high levels of alcohol consumption on liver ADH isozyme phenotype and on rate of alcohol clearance; and 3) to determine the genetic basis of the liver ADH-4 deficiency that exists in some baboons. Baboons with and without liver ADH-4 activity will be selected by analysis of liver biopsy samples, and ethanol infusion experiments will be conducted to determine the rate of ethanol clearance in relation to liver ADH-4 phenotype. Alcohol feeding studies will be undertaken with baboons, using the Lieber-DeCarli liquid diet technique, to determine the influence of moderate and moderately high alcohol consumption on changes in liver ADH phenotype, monitored by liver biopsy, and on changes in ethanol clearance rate determined by ethanol infusion. The genetic basis of ADH-4 deficiency will determined by typing ADH-4 activity levels in liver samples of pedigreed baboons that have been necropsied and of those from which biopsies will be taken for this project. The results of these experimental manipulations, not possible with human subjects, will provide new insights that can be applied to understanding the ways in which heredity and alcohol consumption affect rate of alcohol metabolism in humans.
