METABOLIC BASIS OF CONJUGATED DIENES TOXICITY

共轭二烯毒性的代谢基础

• 批准号: 6342566
• 负责人: Adnan A. Elfarra
• 金额: $ 19.55万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6342566
• 关键词: adduct; blood chemistry; chemical carcinogen; cytochrome P450; diene; environmental toxicology; enzyme activity; gender difference; hepatotoxin; human tissue; laboratory mouse; laboratory rat; myeloperoxidase; renal toxin; species difference; toxicant interaction; toxin metabolism; urinalysis

1,3-Butadiene (BD) is a petrochemical diene used extensively in the manufacture of synthetic rubber and plastics. In 1996, the Occupational Safety and Health Administration (OSHA) reduced the 8-hr time-weighted average workroom standard for BD from 1000 ppm to 1 ppm because human and animal exposure to BD has been associated with development of cancer. Key target tissues, in both humans and animals, include bone marrow, lung, heart, and liver. Mice, which were much more sensitive to BD-induced carcinogenicity than rats, exhibited sex and tissue differences in susceptibility. However, the biochemical basis for BD- induced carcinogenicity remains unclear. We have previously characterized BD oxidation to yield mutagenic metabolites, butadiene monoxide and diepoxybutane, in mouse, rat, and human liver. The results provided evidence for significant species differences in hepatic BD bioactivation and indicated major roles for P450 2E1 and 2A6 in BD oxidation in human liver. However, the sex- related differences in BD bioactivation in mouse, rat, and human tissues have not been investigated. Also, BD bioactivation in other target tissues (heart, lung, and bone marrow) remains unclear. Recently, we have obtained preliminary data indicating a major role for P450 4B1 in BD oxidation in male and female mouse lung and male mouse kidney. Thus, current experimental objectives are: A) To investigate sex-related differences in BD bioactivation in target (lung, heart, bone marrow, and liver) and non-target (kidney) tissues of both mice and rats, investigate the roles of P450s 2A, 2E, and 4B in BD bioactivation in these tissues, and characterize BD bioactivation in male and female human lung and liver. B) To characterize the specific DNA adducts of butadiene monoxide and diepoxybutane that are formed in vivo in various mouse and rat tissues, and investigate their potential role in species, sex, and tissue differences in susceptibility. C) To develop biomonitoring methods to assess exposure of mice and rats to BD, using GC/MS, LC/MS, and postlabeling techniques. These methods will be based upon characterization of covalent adducts of butadiene monoxide with hemoglobin and determinations of concentrations of modified, excised DNA bases in urine. The proposed studies will allow for a better understanding of the mechanisms of BD carcinogenicity and may facilitate and improve human epidemiologic studies. This may lead to a more accurate assessment of human risk.

1,3-丁二烯（BD）是一种广泛使用的石化二烯 制造合成橡胶和塑料。 1996年，职业 安全与健康管理局（OSHA）减少了8小时的时间加权 BD的平均工作室标准从1000 ppm到1 ppm，因为人类 动物暴露于BD与 癌症。 人类和动物的关键靶组织包括骨头 骨髓，肺，心脏和肝脏。 小鼠，更敏感 与大鼠相比，BD诱导的致癌性，表现出性别和组织 易感性的差异。 但是，BD-的生化基础 诱导的致癌性尚不清楚。 我们先前已经表征了BD氧化以产生诱变 代谢物，丁二烯一氧化碳和二氧化丁烷，小鼠，大鼠和 人肝。 结果提供了重要物种的证据 肝BD生物活化的差异，并指出了主要作用 P450 2E1和2A6在人肝脏中的BD氧化中。但是，性 小鼠，大鼠和人体组织中BD生物活化的相关差异 尚未进行调查。 另外，其他目标中的BD生物活化 组织（心脏，肺和骨髓）尚不清楚。 最近，我们 获得了初步数据，表明P450 4B1在 男性和雌性小鼠肺和雄性小鼠肾脏中的BD氧化。 因此， 当前的实验目标是：a）调查与性别相关的目标 靶标BD生物活化的差异（肺，心脏，骨髓和 小鼠和大鼠的肝）和非靶（肾脏）组织 研究P450S 2A，2E和4B在BD生物活化中的作用 这些组织，表征男性和女性的BD生物活化 人肺和肝脏。 b）表征特定的DNA加合物 丁二烯一氧化烷和二氧化烷丁烷在各种体内形成 小鼠和大鼠组织，并研究它们在物种中的潜在作用， 性别和易感性的组织差异。 c）发展 使用生物监测方法评估小鼠和大鼠对BD的暴露 GC/MS，LC/MS和后标签技术。 这些方法将基于 一氧化丁烷的共价加合物的表征 血红蛋白和修饰，切除的DNA浓度的测定 尿液中的碱。 拟议的研究将允许更好 了解BD致癌的机制，并可能有助于 并改善人类流行病学研究。 这可能会导致更多 准确评估人类风险。