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

工作总结：对1，3-丁二烯的两种结构类似物异戊二烯（2-甲基-1，3-丁二烯）和氯丁二烯（2-氯-1，3-丁二烯）的吸入致癌性研究表明了多器官致癌效应，包括1，3-丁二烯致癌性靶点的几个部位。 已经采取了多种研究方法来了解和量化导致这类化学品致癌性的环氧化物形成化学品的影响。这些化学物质诱导的肿瘤ras原癌基因的遗传改变分析显示，K-ras密码子61处的A至T颠换占优势。为了解释仅经鼻吸入暴露于丁二烯后循环环氧丁烯浓度的过度预测，我们修改了丁二烯处置的早期毒代动力学模型，以描述由于该酶和细胞色素P450之间形成瞬时复合物，内质网结合的环氧化物中间体对环氧化物水解酶（特权进入）的可及性增强。在该模型中，结合的环氧化物P450产物与环氧化物释放到胞质溶胶中竞争水解。该模型扩展到包括水解和/或谷胱甘肽共轭丁-3-烯-1，2-二醇，3，4-环氧丁烷-1，2-二醇和1，2; 3，4-二环氧丁烷。该模型再现了从密闭室中观察到的丁二烯和环氧丁烯的摄取，模拟了组织环氧化物浓度和肝脏和肺中谷胱甘肽的消耗，计算的累积代谢物再现了6小时吸入暴露于14 C-丁二烯后42小时在尿液和呼出气中观察到的分布。在肝脏、肺和肾脏中，预测的稳态环氧丁二醇浓度约为环氧丁烯浓度的两倍，这与在丁二烯暴露小鼠和大鼠的这些组织中观察到的N7-鸟苷酸三羟基丁酯加合物多于羟丁基加合物一致。剂量反应模型的生存调整肿瘤数据表明，氯丁二烯在小鼠中的致癌潜力是类似的1，3-丁二烯。

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.