METABOLISM AND TOXICITY OF HYDROQUINONE-THIOETHERS

氢醌硫醚的代谢和毒性

• 批准号: 6342820
• 负责人: Serrine S Lau
• 金额: $ 26.11万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-02-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6342820
• 关键词: adduct; chemical carcinogenesis; environmental exposure; gene environment interaction; gene mutation; genetic susceptibility; glutathione analog; guinea pigs; hydroquinones; laboratory rat; renal cell carcinoma; renal toxin; species difference; thioether; toxin metabolism

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.

描述（逐字摘自研究者摘要）：遗传学鉴定 在职业性或非职业性工作后易患肿瘤的个体中， 环境暴露于潜在的致癌物质需要了解 特定基因如何决定对化学致癌作用的易感性。 了解人群中易感个体的比例， 正常和易感人群的相对癌症易感性将使 有可能估计人类接触致癌物风险。此外，肿瘤 致癌物暴露后的发育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采取 考虑到受致癌物质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遗传限制， 癌症易感性对苯二酚（HQ）是一种致癌物质， 物种和组织的选择性，并在以前的赠款年，我们已经建立了 物种差异存在于对急性影响的敏感性方面， 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 基因决定了生物活化的差异，和/或 易感性因素，包括修复组织损伤的能力， 有助于物种对氢醌诱导的瘤形成的易感性。的 这些变量中的每一个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具有抵抗力， 肾毒性代谢物，2，3，5-（三谷胱甘肽-S-基）HQ。在肾细胞 肾癌（RCC）3号染色体杂合性丢失频繁发生， 在这个假定的肿瘤抑制基因上的改变的遗传倾向于 RCC的发展。在Eker大鼠中，单个基因突变倾向于 具有常染色体显性遗传模式的多发性双侧RCC，以及 携带Eker突变的动物作为遗传性RCC的模型。的 第二个具体目标，在这个修改后的竞争性续期申请将 因此，重点放在遗传倾向和化学之间的相互作用， 在Eker大鼠模型中，暴露对肾癌易感性的影响。整体 该目的的目标是表征Eker动物模型，其中 环境影响（化学品暴露）对遗传的影响 癌症的易感性是确定的。