MECHANISTIC STUDIES ON 1,3-BUTADIENE AND RELATED EPOXIDE-FORMING CHEMICALS

点击翻译按钮获取中文摘要

Summary of Work: Inhalation carcinogenicity studies on two structural analogues of 1,3-butadiene, isoprene (2-methyl-1,3-butadiene) and chloroprene (2-chloro-1,3-butadiene), demonstrated multiple-organ carcinogenic effects including several sites that were targets of 1,3-butadiene carcinogenicity. Multiple research approaches have been taken to understand and quantify the effects of epoxide-forming chemicals that contribute to the carcinogenicity of this family of chemicals. Analyses of genetic alterations in ras protooncogenes in neoplasms induced by these chemicals revealed a predominance of A to T transversions at K-ras codon 61. To account for over-predictions of circulating epoxybutene concentrations after nose-only inhalation exposure to butadiene, our earlier toxicokinetic model of butadiene disposition was modified to describe enhanced accessibility of endoplasmic reticulum-bound epoxide intermediates to epoxide hydrolase (privileged access) due to the formation of a transient complex between that enzyme and cytochrome P450. In this model, bound epoxide P450 products are hydrolyzed in competition with release of the epoxides into the cytosol. The model was extended to include hydrolysis and/or glutathione conjugation of but-3-ene-1,2-diol, 3,4-epoxybutane-1,2-diol, and 1,2;3,4-diepoxybutane. The model reproduced the observed uptake of butadiene and epoxybutene from closed chambers, it simulated tissue epoxide concentrations and depletion of glutathione in liver and lung, and the computed cumulative metabolites reproduced the observed distribution in urine and exhaled breath 42 hr after a 6-hr inhalation exposure to 14C-butadiene. The predicted epoxybutanediol concentration at steady state in liver, lung, and kidney is about double the epoxybutene concentration, consistent with observations of more trihydroxybutyl N7-guanylate adducts than hydroxybutyl adducts in these tissues of butadiene-exposed mice and rats. Dose-response modeling of survival adjusted tumor data demonstrated that the carcinogenic potency of chloroprene in mice is similar to that of 1,3-butadiene.