Genetic and developmental regulation of mouse liver alcohol dehydrogenase

Alcohol dehydrogenase (EC 1.1.1.1; alcohol:NAD+ oxidoreductase) activity varies 2-fold in liver extracts prepared from different inbred mouse strains. The strain-specific variation is not present in kidney extracts of male mice and is developmentally specific in the liver, occurring in mice 25 days of age and older. Neither electrophoretic nor heat lability properties of the enzyme from 15-day-old animals are different from the enzyme in adult mice. Analysis of genetic crosses and recombinant inbred lines confirms that a single genetic locus, designated Adh-1-t, with additive alleles has a major effect in controlling the temporal difference in enzyme activity between strains. This enzyme has been purified from mouse liver, and antibodies to the enzyme have been produced in a goat. Quantitative immunoprecipitation reveals that a given quantity of antibody immunoprecipitates equivalent protein and enzyme activity from liver extracts prepared from high and low strain mice and from 5-day-old and adult mice. Enzyme from high and low strains can be purified to the same specific activity and has indistinguishable electrophoretic and heat denaturation properties. This evidence supports the hypothesis that the high liver activity in C57BL/6 mice is due to the presence of more enzyme molecules/g of liver than is found in low activity mice. Using radiolabeling and specific immunoprecipitation of alcohol dehydrogenase, it has been established that high level mice (C57BL/6) have a 2-fold greater relative rate of synthesis of liver alcohol dehydrogenase than is found in low strain mice (C3H). Thus, the action of the Adh-1-t locus in the mouse is to control the level of alcohol dehydrogenase protein in the liver by controlling the rate of synthesis of this enzyme.