The basis for this project is the hypothesis that certain individuals with normally benign moderate deficiencies in metabolism of xenobiotic compounds may be predisposed to high risk from exposure to carcinogens, mutagens, or hormone therapy. The hypothesis will be tested using a new and unique mouse mutation (hub) that we have identified and characterized as a deficiency in UDP-glucuronosyltransferase activity; the enzyme is part of a multisubstrate family responsible for metabolism of many endogenous and exogenous compounds. The mutation is identified by an autosomal recessive transient neonatal jaundice. The deficiency is nonacute and lifelong; Gilberts's syndrome is a close parallel in the human population. We have determined that recessive females have elevated estradiol levels and that affected individuals of both sexes have liver hyperplasia associated with increased mitosis, cytomegaly, and single cell necrosis; a pleiotropic characteristic that has particular interest, is the presence of many hepatic eosinophilic (preneoplastic) foci. Our goals are to 1) determine the effect of the deficiency on spontaneous and induced mutagenesis by producing transgenic animals containing a marker for mutation and 2) ask whether deficient individuals are hypersensitive to tumorgenesis. If there is marked hypersensitivity, then these animals may be a useful genetic model for defining factors involved in tumor progression. Mice carrying the recessive deficiency have been made transgenic for a mutation marker by cross with mice homozygous for a phiX174 phage marker. Mice that are homozygous for both the deficiency and the marker will be used to investigate the potential for increased sensitivity to both mutagenic and carcinogenic agents among deficient individuals as a function of dose and development stage.
