TOXICOLOGICAL SIGNIFICANCE OF ALKYLBENZENE METABOLISM

烷基苯代谢的毒理学意义

• 批准号: 3465167
• 负责人: WAYNE L BACKES
• 金额: $ 7.68万
• 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/3465167
• 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.

该项目的长期目标是提供信息 这将有助于确定在何种条件下 个体可能对烷基苯引起的毒性敏感。 单环芳烃是产生的化合物 全世界范围内数量巨大。 化合物 ,e 该提案审查了甲苯、二甲苯、乙苯和 正丙苯是汽油的主要成分，其含量高达 产品的40%。 美国甲苯产量 二甲苯和乙苯分别约为60亿、50亿和8 十亿英镑，分别将这些化合物排名 前 10 名化学品。 这些化合物广泛用作溶剂 特别是使用“安全”的甲苯和二甲苯 苯的替代品。 这些化合物被释放到 主要通过汽车尾气和汽车尾气造成的损失 炼油厂，导致频繁暴露 光化学烟雾。 烷基苯对环境的损失 估计有1220万吨，其中一半以上已释放 来自甲苯。 这些化合物的毒性作用包括 麻醉、肝、肾和心脏损害，这些损害可以从以下方面明显看出： 急性和慢性接触这些化合物。 排毒 烷基苯涉及微粒体电子传递 系统，其中末端氧化酶细胞色素 P-450 催化 这些化合物的脂肪族和芳香族氧化。 这 该项目要实现的具体目标包括：(1) 鉴定代谢命运的变化 由于先前施用而产生烷基苯。 这些研究 将重点关注产生的代谢物，无论是先前的 管理影响侧链的相对量 芳香族羟基化，以及每种烷基苯是否会诱导 独特的细胞色素 P-450 同工酶，可催化其氧化。 (2) 年龄、性别和品系差异的影响以及 暴露时间和暴露于碳氢化合物混合物的影响将 被检查。 (3)碳氢化合物对细胞色素的诱导作用 P-450 对烷基苯与酶的结合将 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 碳氢化合物可抑制细胞色素 P-450 依赖性反应。 这些研究不仅有助于安全评估 这个重要的类别如果化合物，但也将有助于 酶系统的基本知识 代谢。