METABOLISM AND TOXICITY OF HYDROQUINONE-THIOETHERS

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DESCRIPTION (Verbatim from Investigator's Abstract): Identification of genetic markers in individuals predisposed to tumor development after occupational or environmental exposure to potential carcinogens requires an understanding of how specific genes determine susceptibility to chemical-induced carcinogenesis. Knowledge of the proportion of susceptible individuals in the population and the relative cancer susceptibility of normal and predisposed groups will make it possible to estimate human risk from carcinogen exposure. In addition, tumor development after carcinogen exposure often exhibits tissue specificity. Studies on the genetic basis of carcinogen susceptibility must therefore take into account both the specific tissue and cell type affected by the carcinogen and genetic restrictions that may exist in various cell types that effect cancer susceptibility. Hydroquinone (HQ) is a carcinogen that exhibits both species and tissue selectivity, and in prior grant years we have established that species differences exist in susceptibility to the acute effects of the nephrotoxic metabolites of HQ. We will extend these findings to identify the genetic/molecular basis for these differences. In Specific Aim 1 we hypothesize that genetically determined differences in bioactivation, and/or presence of susceptibility factors, including the ability to repair tissue damage, contribute to species susceptibility to hydroquinone induced neoplasia. The molecular control of each of these variables will be determined in species susceptible or resistant to both the acute and chronic effects of HQ, and its nephrotoxic metabolite, 2,3,5-(trisglutathion-S-yl)HQ. In human renal cell carcinoma (RCC) loss of heterozygosity of chromosome 3 occurs frequently, and inheritance of an alteration at this putative tumor suppressor predisposes to the development of RCC. In Eker rats, a single gene mutation predisposes to multiple bilateral RCCs with an autosomal dominant pattern of inheritance, and animals carrying the Eker mutation serve as a model for hereditary RCC. The second Specific Aim in this revised competing renewal application will therefore focus on the interaction between genetic predispositions and chemical exposure on susceptibility to renal cancer, in the Eker rat model. The overall goals of this aim are to characterize the Eker animal model in which the effects of environmental influences (chemical exposure) on a genetic predisposition to cancer are determined.