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

工作总结：1，3-丁二烯的两个结构类似物--异戊二烯(2-甲基-1，3-丁二烯)和氯丁二烯(2-氯-1，3-丁二烯)的吸入致癌研究证实了多器官致癌作用，包括作为1，3-丁二烯致癌靶点的几个部位。已采取多种研究方法来了解和量化环氧化物形成化学品的影响，这些化学品有助于这一类化学品的致癌作用。对这些化学物质诱导的肿瘤中ras原癌基因的遗传变化的分析表明，在K-ras密码子61处，A到T的转换占主导地位。为了解释鼻部吸入暴露于丁二烯后循环中环氧丁烯浓度的过度预测，我们早期的丁二烯处置毒代动力学模型被修改为描述由于内质网结合的环氧化物中间体对环氧化物水解酶(特权访问)的增强可及性，这是由于该酶与细胞色素P450之间形成了瞬时络合物。在这个模型中，结合的环氧化物P450产物被竞争地水解，环氧化物被释放到胞浆中。模型被扩展到包括丁烯-1，2-二醇、3，4-环氧丁烷-1，2-二醇和1，2；3，4-二环氧丁烷的水解和/或谷胱甘肽共轭。该模型再现了观察到的丁二烯和环氧丁烯从密闭室中的摄取，它模拟了组织环氧化物的浓度以及肝脏和肺中谷胱甘肽的消耗，计算的累积代谢物再现了14C-丁二烯吸入42小时后尿液和呼气中观察到的分布。在肝脏、肺和肾脏中预测的稳态环氧丁二醇浓度大约是环氧丁烯浓度的两倍，这与在接触丁二烯的小鼠和大鼠的这些组织中观察到更多的三羟丁基N7-鸟苷加合物而不是羟丁基加合物是一致的。生存校正肿瘤数据的剂量-反应模型表明，氯丁二烯在小鼠体内的致癌效力与1，3-丁二烯相似。

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.