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

工作概述：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，它们具有多器官致癌作用，包括一些部位是1,3-丁二烯致癌性的靶点。已经采取了多种研究方法来了解和量化环氧化物形成化学物质的影响，这些化学物质有助于这类化学物质的致癌性。对这些化学物质诱导的肿瘤中ras原癌基因的遗传改变的分析显示，K-ras密码子61的a到T转换占主导地位。测定了特定环氧化物（包括丁二烯代谢的两种环氧化物中间体）与DNA的反应速率常数和环氧化物-DNA加合物的自发释放动力学。利用文献数据，构建了三个不同解剖细节程度的PBPK模型，并用于预测1,3-bautadiene从封闭腔室的摄取。只有当血液分布在动脉、静脉和组织毛细血管床上时，模型才能准确地再现数据，这表明通常的流向组织受限的假设可能不适用于该化合物。通过考虑产生环氧丁烯的细胞色素P450酶和催化这种诱变中间体水解的环氧化物水解酶之间形成的短暂复合物，成功地改进了变异丁二烯模型。该复合物增强了环氧丁烯的代谢消除，并纠正了通过不太详细的模型预测的血液环氧化物浓度的过度预测。建立了基于生理的吸入异戊二烯毒性动力学模型，为评价异戊二烯在大鼠体内的肿瘤剂量-反应数据提供了合适的剂量度量。经生存校正肿瘤数据的剂量-反应模型表明，氯丁烯在小鼠中的致癌效力与1,3-丁二烯相似。-环氧化物、致癌作用、DNA反应性、去嘌呤、ras原癌基因、DNA修复、1,3-丁二烯、氯丁烯、异戊二烯、环氧乙烷

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. Rate constants of the reactivity of specific epoxides (including the two epoxide intermediates of butadiene metabolism) with DNA and the kinetics of spontaneous release of epoxide-DNA adducts were determined. Using literature data, three PBPK models differing in their degree of anatomical detail were constructed and used to predict uptake of 1,3-bautadiene from closed chambers. Only when blood was distributed among arteries, veins, and tissue capillary beds would the model accurately reproduce the data, suggesting that the common assumption of flow-limited delivery to tissues may not be appropriate for this compound. The successful variant butadiene model was improved by accounting for a transient complex formed between the cytochrome P450 enzyme that produces epoxybutene and epoxide hydrolase, the enzyme that cartalyzes the hydolysis of this mutagenic intermedaite. This complex enhances the metabolic elimination of epoxybutene and corrected the over-prediction of blood epoxide concentrations that were predicted by less detailed models. A physiologically based toxicokinetic model of inhaled isoprene was constructed to provide an appropriate measure of dose for evaluations tumor dose-response data of isoprene in 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. - epoxides, carcinogenesis, DNA reactivity, depurination, ras protooncogenes, DNA repair, 1,3-butadiene, chloroprene, isoprene, ethylene oxide