TOXICOLOGICAL SIGNIFICANCE OF ALKYLBENZENE METABOLISM

本提案的长期目标是提供信息， 将有助于确定个人可能 对烷基苯引起的毒性敏感。烷基苯 在世界各地大量生产。简单芳族 烃类（例如苯、甲苯、二甲苯、丙苯 和丁基苯）是无铅汽油的主要成分， 而不是铅来提高辛烷值除了它们 由于存在于汽油中，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、澄清剂和其他 化合物.据报道，苯是最危险的化学品之一， 小芳烃由于其代谢的芳香 通过反应性环氧化物中间体进行羟基化。烷基苯，如 甲苯和二甲苯已被广泛用作 苯，因为它们被认为是通过侧链代谢的 羟基化（约99%），芳族羟基化是 小通道。烷基苯由细胞色素P450代谢 系统，负责脂肪族和芳香族羟基化 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 芳族羟基化包括高达25%的观察到的产物。 这些化合物代谢的变化是诱导的结果 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 烷基苯暴露。因此，这些表达的变化 同工酶将对烷基苯的代谢产生深远的影响 以及其他外来化合物。结果表明，诱导 P450同工酶的活性并不简单地依赖于化合物， 个人是暴露的，但也对他们的曝光模式。目标 这项建议的目的是检查调节P450同工酶的调节， 烷基苯暴露。将讨论三个具体目标。（一） 细胞色素P450同功酶对激素的调节作用 烷基苯管理将被审查，重点是作用， 生长激素在调节烷基苯介导的 P450 2B 1/2B 2、2C 11、2 E1和3A 1/3A 2的表达。(2)血红素的作用 在功能性P450同工酶的诱导将被检查。这些 研究将集中在潜在的能力， 细胞血红素水平，从而降低诱导程度 P450 2B同工酶。(3)接触烷基苯对大鼠脑组织的影响 检测P450在脑中的表达。这些研究将侧重于 假设烷基苯的某些中枢神经系统效应可能是 通过羟基化烷基苯代谢物介导， 脑中代谢物的产生受先前烷基苯的调节， exposure.这些研究不仅应该有助于一个基本的 了解调节这些酶表达的因素，但 还可以提供有助于识别 与烷基苯毒性相关的个体状况 生长激素分泌或血红素状态改变。此外，委员会认为， 这些研究有望提供有助于 表征P450在脑中的表达，并将其与代谢 烷基苯对这些药物的中枢神经系统的影响。

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.