Conjugated dienes such as 1,3-butadiene, 2-methyl-1,3-butadiene (isoprene), and cyclopentadiene are extensively used in the rubber, plastics and pesticide industries. Exposure of mice and rats to 1,3-butadiene results in lesions in gonads, lung and liver. In addition, maternal toxicity, fetotoxicity and the formation of tumors in multiple organs have been observed. Mice are much more susceptible to the toxic effects of 1,3-butadiene compared to rats. Current evidence implicates the metabolism of 1,3- butadiene by the mixed-function oxidases to yield the chemically reactive butadiene monoxide and diepoxybutane in the mechanisms of 1,3-butadiene-induced toxicity. The broad objectives of the proposed research are to elucidate pathways of metabolic activation and detoxification of conjugated dienes, and to characterize the biochemical and chemical mechanisms by which conjugated dienes exert toxicological effects. This information is needed in order to understand the biochemical basis of target-organ selectivity and species variability. Specific experimental objectives are as follows: 1) To investigate the role of peroxidases, prostaglandin endoperoxide synthetase and cytochrome P-450-dependent monoxygenases in the metabolism of conjugated dienes to form reactive epoxides. 2) To investigate the possibility that reactive oxidative metabolitese other than the epoxides (reactive aldehydes and ketones) may be formed. 3) To determine the role of glutathione in the metabolism and toxicity of conjugated dienes. 4) To determine the role of epoxide hydrolase and aldehyde and alcohol dehydrogenases in the metabolism and toxicity of conjugated dienes. 5) To characterize the in vivo and in vitro interactions of the reactive metabolites with cellular protein and nucleic acids. This will include an investigation of the possible inactivation of enzymes involved in the bioactivation of conjugated dienes by the generated reactive metabolites.
| Elfarra, A A; Krause, R J; Selzer, R R (1996) Biochemistry of 1,3-butadiene metabolism and its relevance to 1,3-butadiene-induced carcinogenicity. Toxicology 113:23-30 |
