TOXICOLOGICAL SIGNIFICANCE OF ALKYLBENZENE METABOLISM

烷基苯代谢的毒理学意义

• 批准号: 2701299
• 负责人: WAYNE L BACKES
• 金额: $ 18.6万
• 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 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2701299
• 关键词: benzene; brain; carbopolycyclic compound; cytochrome P450; enzyme activity; enzyme induction /repression; gene expression; heme; high performance liquid chromatography; immunocytochemistry; isozymes; laboratory rat; neurotoxicology; northern blottings; nuclear runoff assay; polymerase chain reaction; protein structure function; scintillation counter; somatotropin; statistics /biometry; tissue /cell culture; toxicant interaction; toxin metabolism

The long term objective of this proposal is to supply information that will aid in the identification of conditions under which individuals might be susceptible to alkylbenzene-induced toxicity. Alkylbenzenes are produced in extensive quantities throughout the world. Simple aromatic hydrocarbons (e.g. benzene, toluene, ethylbenzene, xylenes, propylbenzenes and butylbenzenes) are major components of unleaded gasoline, and are used instead of lead to increase the octane rating. In addition to their presence in gasolines, these compounds are also used in the production of a wide variety of consumer products including paints, solvents, perfumes, dyes, plasticizers, resins, insecticides, adhesives, deodorants, and other compounds. Benzene has been reported to be one of the most hazardous of the small aromatic hydrocarbons due to its metabolism by aromatic hydroxylation via reactive epoxide intermediates. Alkylbenzenes such as toluene and the xylenes have been widely used as safe substitutes for benzene, since they were believed to be metabolized by side chain hydroxylation (approximately 99%) with aromatic hydroxylation being a minor pathway. The alkylbenzenes are metabolized by the cytochrome P450 system, which is responsible for both aliphatic and aromatic hydroxylation reactions. When rats are exposed to these simple alkylbenzenes, there is a dramatic increase in the hepatic alkylbenzene metabolism, resulting in aromatic hydroxylation comprising up to 25% of the observed products. Changes in the metabolism of these compounds are the result of induction of specific cytochrome P450 isozymes. Previous results indicate that the levels of several P450 isozymes are temporally expressed after continued alkylbenzene exposure. Consequently, changes in the expression of these isozymes will have a profound influence on the metabolism of alkylbenzenes as well as other foreign compounds. The results suggest that the induction of P450 isozymes is not simply dependent on the compounds to which an individual is exposed, but also on the pattern of their exposure. The goal of this proposal is to examine regulation of the P450 isozymes modulated by alkylbenzene exposure. Three specific aims will be addressed. (1) Hormonal modulation of cytochrome P450 isozymes in response to alkylbenzene administration will be examined, focussing on the role of growth hormone in modulating the alkylbenzene-mediated changes in the expression of P450 2B1/2B2, 2C11, 2E1, and 3A1/3A2. (2) The role of heme in the induction of functional P450 isozymes will be examined. These studies will focus on the potential ability of ethylbenzene to suppress cellular heme levels and consequently to depress the degree of induction of P450 2B isozymes. (3) The effect of alkylbenzene exposure on the expression of P450 in brain will be examined. These studies will focus on hypothesis that some of the CNS effects of the alkybenzenes may be mediated via hydroxylated alkylbenzene metabolites, and that the production of the metabolites in brain is modulated by prior alkylbenzene exposure. These studies should not only contribute to a fundamental understanding of factors regulating the expression of these enzymes, but may also provide information which will be useful in identifying conditions related to alkylbenzene toxicity in individuals with variations in growth hormone secretion or alterations in heme status. Furthermore, these studies are expected to provide information helpful in characterizing P450 expression in brain, and correlating the metabolism alkylbenzenes to the CNS effects of these drugs.

这项提案的长期目标是提供以下信息 将有助于确定在哪些情况下个人可能 易受烷基苯致毒性。烷基苯是 在世界各地大量生产。简单芳香族 碳氢化合物(如苯、甲苯、乙苯、二甲苯、丙基苯 和丁苯)是无铅汽油的主要成分，用于 而不是铅来提高辛烷值。除了他们的 存在于汽油中，这些化合物也用于生产 各种各样的消费品，包括油漆、溶剂、香水、 染料、增塑剂、树脂、杀虫剂、粘合剂、除臭剂等 化合物。据报道，苯是最危险的 芳香族代谢产生的小分子芳香烃 通过反应性环氧化物中间体进行羟化反应。烷基苯，如 甲苯和二甲苯已被广泛用作安全的替代品 苯，因为它们被认为是通过侧链代谢的 羟化(约99%)，芳香族羟化是 次要途径。烷基苯类被细胞色素P450代谢 负责脂肪族和芳香族羟化反应的体系 反应。当老鼠暴露在这些简单的烷基苯中时， 肝脏烷基苯代谢急剧增加，导致 芳香族羟基化反应占观察到的产物的25%。 这些化合物的新陈代谢变化是诱导的结果。 特异性细胞色素P450同工酶。先前的结果表明， 几种P450同工酶的水平在持续的时间内表达 接触烷基苯。因此，这些基因表达的变化 同工酶将对烷基苯类的代谢产生深远的影响 以及其他外国化合物。结果表明，诱导 P450同工酶的活性并不是简单地依赖于 个体是暴露的，也是对其暴露的模式。目标是 这项建议的目的是研究P450同工酶的调节 通过接触烷基苯。将解决三个具体目标。(1) 细胞色素P450同工酶的激素调节作用 将审查烷基苯的给药，重点是烷基苯的作用 生长激素在调节烷基苯介导的细胞周期变化中的作用 P450 2B1/2B2、2C11、2E1和3A1/3A2的表达。(2)血红素的作用 在功能诱导中，将检测P450同工酶。这些 研究将集中在乙苯的潜在抑制能力上。 细胞内的血红素水平，从而抑制诱导程度 P4502B同工酶。(3)接触烷基苯对机体功能的影响 检测脑组织中P450蛋白的表达。这些研究将集中在 假设烷基苯的某些中枢神经系统效应可能是 通过羟基烷基苯代谢物进行调节，并且 脑内代谢物的产生受前烷基苯的调节 曝光。这些研究不仅应该有助于 对调控这些酶表达的因素的了解，但 还可以提供有助于识别 不同个体中与烷基苯中毒相关的条件 生长激素分泌或血红素状态的改变。此外， 预计这些研究将提供有助于 P450在脑内的表达特征及其与代谢的关系 烷基苯类药物对中枢神经系统的影响。