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

1,3-丁二烯及相关环氧化物形成化学品的机理研究

• 批准号: 6162329
• 负责人: R L MELNICK
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6162329
• 关键词: carcinogen testing; chemical carcinogen; chemical carcinogenesis; chemical structure function; epoxides; mutagen testing; mutagens; pharmacokinetics

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=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.

工作总结：两种结构的吸入致癌性研究 1，3-丁二烯、异戊二烯(2-甲基-1，3-丁二烯)和 氯丁二烯(2-氯-1，3-丁二烯) 致癌作用，包括作为目标的几个部位 1，3-丁二烯致癌。已经有了多种研究方法 用来理解和量化形成环氧化物的化学物质的影响 导致这类化学物质致癌的物质。 肿瘤中ras原癌基因的遗传改变分析 由这些化学物质诱导的结果显示A=T转换占优势 K-ras密码子61。特定环氧化物反应活性的速率常数 (包括丁二烯代谢的两种环氧化物中间体) DNA和环氧化物-DNA加合物的自发释放动力学 下定决心。使用文献数据，三种不同的PBPK模型 解剖细节的程度被构建并用于预测摄取 从密闭室中提取1，3-丁二烯。只有当血液被分配到 动脉、静脉和组织毛细血管床之间的模型 准确地复制数据，表明通常的假设是 对组织的限流递送可能不适合这种情况 化合物。