TOXICOLOGICAL SIGNIFICANCE OF ALKYLBENZENE METABOLISM

烷基苯代谢的毒理学意义

基本信息

批准号：
2153657
负责人：
WAYNE L BACKES
金额：
$ 10.5万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-01-15 至 1994-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2153657
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

项目摘要

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条件个体可能容易受到烷基苯诱导的毒性的影响。单核芳族烃是产生的化合物全世界大量数量。这些化合物在此提案中检查了甲苯，二甲苯，乙烯苯和 N-丙烯苯是汽油的主要组成部分，包括产品的40％。美国生产甲苯，二甲苯和乙烯苯大约为60亿，50亿和8 分别将这些化合物分别排名十亿英镑前十种化学物质。这些化合物被广泛用作溶剂特别是甲苯和二甲苯，它们用作“安全” 替代苯。这些化合物已释放到环境主要通过汽车的排气和损失炼油厂，导致经常以光化学烟雾。烷基苯损失对环境的损失估计为1220万吨，释放一半以上来自甲苯。这些化合物的毒性作用包括麻醉，肝脏，肾脏和心脏损伤，从急性和慢性暴露于这些化合物。解毒烷基苯烯涉及微粒体电子传输系统，其中末端氧化酶细胞色素P-450都催化这些化合物的脂肪族和芳族氧化。这该项目中要解决的具体目标包括：（1）鉴定代谢命运的变化烷基苯烯由于其先前的给药。这些研究是否将重点放在产生的代谢产物上，无论是否先验管理会影响侧链的相对量与芳族羟基化以及每种烷基苯是否诱导A 独特的细胞色素P-450同工酶催化其氧化。（2）年龄，性别和应变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）细胞色素烃诱导的影响烷基苯甲酸与酶的关联的P-450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抑制细胞色素P-450依赖性反应。这些研究不仅在安全评估中有用如果有复合的话，这个重要的班级，但也会有助于涉及其酶系统的基本知识代谢。