TOXICOLOGICAL SIGNIFICANCE OF ALKYLBENZENE METABOLISM

烷基苯代谢的毒理学意义

• 批准号: 3465168
• 负责人: WAYNE L BACKES
• 金额: $ 9.05万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-01-15 至 1992-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3465168
• 关键词: air pollution; alkyl group; benzene; carbopolycyclic compound; cytochrome P450; drug administration rate /duration; engine exhaust; environmental contamination; heart disorder; kidney disorder; laboratory rabbit; laboratory rat; liver disorder; occupational hazard; photochemistry; solvents; toluene; toxin metabolism

The long term objective of this project is to supply information that will aid in the identification of conditions under which individuals might be susceptible to alkylbenzene-induced toxicity. Monocyclic aromatic hydrocarbons are compounds that are produced in enormous quantities throughout the world. The compounds to ,e examined in this proposal, toluene, the xylenes, ethylbenzene and n-propylbenzene are major components of gasoline comprising up to 40% of the product. United States production of toluene, the xylenes and ethylbenzene are about 6 billion, 5 billion and 8 billion pounds, respectively, ranking each of these compounds among the top 10 chemicals. These compounds are widely used as solvents particularly toluene and xylene which are used as "safe" substitutes for benzene. These compounds are released into the environment primarily through automobile exhausts and losses from refineries, leading to frequent exposure in the form of photochemical smog. Alkylbenzene losses to the environment have been estimated at 12.2 million tons with over half of the release from toluene. The toxic effects of these compounds include narcosis, liver, kidney and heart damage which are evident from both acute and chronic exposure to these compounds. Detoxification of the alkylbenzenes involves the microsomal electron transport system, where the terminal oxidase cytochrome P-450 catalyzes both the aliphatic and aromatic oxidations of these compounds. The specific aims to be addressed in this project include: (1) Identification of changes in the metabolic fate of the alkylbenzenes due to their prior administration. These studies will focus on the metabolites produced, whether prior administration affects the relative amounts of side chain versus aromatic hydroxylation, and whether each alkylbenzene induces a unique cytochrome P-450 isozyme which catalyzes its oxidation. (2) The effects of age, sex and strain differences as well as the effects of exposure time and exposure to hydrocarbon mixtures will be examined. (3) The effect of hydrocarbon induction of cytochrome P-450 on the association of the alkylbenzenes with the enzyme will be determined by measuring spectral binding to cytochrome P-450, substrate effects on first electron input, and the ability of hydrocarbons to inhibit cytochrome P-450 dependent reactions. These studies will not only be useful in the safety assessment of this important class if compounds, but will also contribute to a fundamental knowledge of the enzyme system involved in their metabolism.

这个项目的长期目标是提供信息 这将有助于确定在什么情况下 个体可能对烷基苯引起的毒性敏感。 单环芳香族碳氢化合物是一种 在世界各地数量巨大。复合词to，e 本提案中审查的甲苯、二甲苯、乙苯和 正丙苯是汽油的主要成分，包括 40%的产品。美国的甲苯生产， 二甲苯和乙苯分别约为60亿、50亿和8亿 10亿英镑，使这些化合物中的每一种都在 排名前十的化学物质。这些化合物被广泛用作溶剂。 尤其是甲苯和二甲苯，它们被认为是“安全的” 苯的替代品。这些化合物被释放到 环境主要是通过汽车尾气和 炼油厂，导致以以下形式频繁暴露 光化学烟雾。烷基苯对环境的损失有 估计有1220万吨，超过一半的释放 从甲苯中提取。这些化合物的毒性作用包括 麻醉、肝、肾和心脏损害，从 急性和慢性接触这些化合物。解毒解毒 烷基苯类的电子传递涉及到微粒体的电子传递 系统，其中末端氧化酶细胞色素P-450催化这两个 这些化合物的脂肪族和芳香族的氧化。这个 本项目的具体目标包括：(1) 确定人的代谢命运的变化 烷基苯类由于其先前的给药。这些研究 将重点放在产生的代谢物上，无论是在 给药影响侧链的相对量与 芳香族羟基化，以及每个烷基苯是否会诱导 催化其氧化的独特的细胞色素P-450同工酶。 (2)年龄、性别和品系差异的影响以及 接触时间和接触碳氢化合物混合物的影响将 接受检查。(3)细胞色素的碳氢化合物诱导效应 P-450对烷基苯类与酶结合的影响 通过测量与细胞色素P-450的光谱结合来确定， 底物对第一电子输入的影响，以及 碳氢化合物抑制细胞色素P-450依赖的反应。 这些研究不仅将对安全评估有用， 这个重要的类如果是复合的，还将有助于 对其所涉及的酶系统的基础知识 新陈代谢。