Role of metabolism in toxicity of inhaled 1,3 butadiene

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1,3-Buitadiene is a widely used chemical in the manufacture of synthetic rubber and other polymers. It is carcinogenic in mice and rats and is a probable human carcinogen. It is genotoxic and mutagenic in several test systems including mammalian cell culture and mice as well as occupationally exposed humans. Butadiene epoxide metabolites appear responsible for its carcinogenic and mutagenic effects. Studies suggest that humans with a polymorphic deficiency of glutathione-S-transferase T1 may be more sensitive to the genotoxic effects of butadiene. One goal of this proposal is to evaluate the role of butadiene metabolism in the genotoxicity of butadiene in mice. We hypothesize that increased oxidative metabolism and/or diminished conjugation of metabolism with glutathione will increase the toxicity of butadiene in mice. A second goal is to examine the role of nucleotide excision repair (NER) in butadiene- induced mutagenesis using NER deficient mice, hypothesizing that defective NER will increase the susceptibility of mice to DNA damage and mutation. A third goal will be to evaluate how modifications in metabolism and DNA repair will modify the spectrum of mutations induced by butadiene, hypothesizing that these modifications will alter the relative frequencies of specific types of mutations. The specific of the project are to 1) to measure the dose-response in mice to mutations in lymphocytes and DNA damage in lungs after exposure to low, doses of inhaled butadiene; 2) to determine how increased cytochrome P450 2El or decreased glutathione levels effect the genotoxicity and metabolism of butadiene; 3) to determine the role of nucleotide excision repair in the genotoxicity of butadiene using mice containing knockout mutations of the XPA and XPC genes; and 4) determine the spectrum of mutations in the hprt locus in lymphocytes from mice treated as described above. By better characterizing the role of metabolism and DNA repair in its butadiene-induced genotoxicity in mice we anticipate that we will be able to make more informed interpretations of the roles of high frequency polymorphic variants of metabolizing and DNA repair genes in human risk from butadiene exposure.