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 abnormally high risk from exposure to carcinogens, mutagens, or hormone therapy. The mutation is characterized by an autosomal recessive transient neonatal jaundice. Affected individuals of both sexes have liver hyperplasia associated with increased mitosis, cytomegaly, single cell necrosis, and the presence of many hepatic eosinophilic foci. Mice carrying the recessive deficiency have been made transgenic for a recoverable phage mutation marker. It was also recently determined that there was profound increase in the spontaneous cancer incidence among homozygous animals compared with heterozygous littermates of the same age.
Additional evidence suggests a potential deficiency in metabolism of estrogenic compounds.
In FY 1997, deficient animals will be treated with a simple alkylating agent and a model environmental mutagen cleared by glucuronidation to characterize patterns of metabolism and DNA adduction in correlation with any potential for accelerated cancer incidence among deficient animals.