METABOLIC BASIS OF CONJUGATED DIENES TOXICITY

共轭二烯毒性的代谢基础

• 批准号: 6489866
• 负责人: Adnan A. Elfarra
• 金额: $ 20.13万
• 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/6489866
• 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) 是一种石化二烯，广泛用于 合成橡胶和塑料的制造。 1996年，职业 安全与健康管理局 (OSHA) 减少了 8 小时时间加权 BD 的平均工作室标准从 1000 ppm 降至 1 ppm，因为人类 动物接触 BD 与以下疾病的发生有关： 癌症。 人类和动物的关键靶组织包括骨 骨髓、肺、心脏和肝脏。 老鼠更加敏感 BD 诱导的致癌性高于大鼠，表现出性别和组织 易感性的差异。 然而，BD-的生化基础 致癌性尚不清楚。 我们之前已经描述了 BD 氧化产生诱变的特征 小鼠、大鼠和小鼠体内的代谢物一氧化丁二烯和二环氧丁烷 人类肝脏。 结果为重要物种提供了证据 肝 BD 生物活性的差异以及表明的主要作用 人肝脏中 BD 氧化中的 P450 2E1 和 2A6。然而，性别—— 小鼠、大鼠和人体组织中 BD 生物活性的相关差异 尚未被调查。 此外，BD 对其他靶点的生物活性 组织（心脏、肺和骨髓）仍不清楚。 最近，我们 已获得初步数据表明 P450 4B1 在 雄性和雌性小鼠肺和雄性小鼠肾中的 BD 氧化。 因此， 当前的实验目标是：A）调查与性别相关的 BD 生物活性在靶标（肺、心脏、骨髓和 小鼠和大鼠的肝脏）和非目标（肾脏）组织， 研究 P450s 2A、2E 和 4B 在 BD 生物激活中的作用 这些组织，并表征男性和女性的 BD 生物活性 人类的肺和肝脏。 B) 表征特定的 DNA 加合物 一氧化丁二烯和二环氧丁烷在体内以各种形式形成 小鼠和大鼠组织，并研究它们在物种中的潜在作用， 性别和组织的易感性差异。 C) 发展 评估小鼠和大鼠暴露于 BD 的生物监测方法，使用 GC/MS、LC/MS 和后标记技术。 这些方法将基于 一氧化丁二烯与一氧化丁二烯的共价加合物的表征 血红蛋白和修饰、切除 DNA 浓度的测定 尿液中的碱基。 拟议的研究将有助于更好地 了解 BD 致癌机制并可能有助于 并改进人类流行病学研究。 这可能会导致更多 准确评估人类风险。