METABOLISM AND TOXICITY OF HYDROQUINONE-THIOETHERS

描述(逐字摘自研究人员摘要)：基因的鉴定 职业或职业后易患肿瘤的个体的标志物 在环境中暴露于潜在致癌物需要了解 特定基因如何决定化学致癌的易感性。 了解易感人群的比例，以及 正常人群和易感人群的相对癌症易感性将使 估计人类接触致癌物的风险是可能的。此外，肿瘤 致癌物暴露后的发展通常表现出组织特异性。 因此，对致癌物易感性的遗传基础的研究必须 考虑到致癌物影响的特定组织和细胞类型 以及可能存在于各种细胞类型中的基因限制 癌症易感性。对苯二酚(HQ)是一种致癌物质，既表现出 物种和组织的选择性，在之前的赠款年份，我们已经建立了 不同物种对沙门氏菌急性影响的易感性存在差异 HQ的肾毒性代谢物。我们将扩展这些发现，以确定 这些差异的遗传/分子基础。在具体目标1中，我们假设 由基因决定的生物激活和/或存在的差异 易感因素，包括修复组织损伤的能力， 有助于物种对对苯二酚诱导的肿瘤的易感性。这个 这些变量中每个变量的分子控制将在物种中确定 对HQ的急性和慢性影响敏感或抵抗，其 肾毒性代谢物，2，3，5-(三谷硫磷-S基)HQ。在人肾细胞中 肾细胞癌(RCC)3号染色体杂合性缺失是常见的疾病， 这一假定的肿瘤抑制基因突变的遗传易患 碾压混凝土的发展。在Eker大鼠中，单个基因突变容易患上 具有常染色体显性遗传模式的多个双边RCC，以及 携带Eker突变的动物是遗传性肾细胞癌的模型。这个 这份修订后的竞争对手续签申请的第二个具体目标是 因此，重点关注遗传易感性和化学物质之间的相互作用 在Eker大鼠模型中，暴露对肾癌易感性的影响。整体而言 这一目标的目的是描述Eker动物模型的特征，在该模型中 环境影响(化学物质暴露)对基因的影响 癌症的易感性是确定的。

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.