TOXICOLOGICAL SIGNIFICANCE OF ALKYLBENZENE METABOLISM

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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.