GENETIC MARKERS FOR ALCOHOL METABOLISM

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.