MINORITY PREDOCTORAL FELLOWSHIP PROGRAM

在这个项目中，铁的作用将在产生 雌激素氧化还原循环产生的反应性羟基自由基及其在体内的作用 雌激素诱导的致癌。在西化社会中，过量的铁 是通过膳食补充剂摄入的。然而，癌症风险的增加 在人体中与体内铁的储存量高有关。假设是 由代谢氧化还原循环产生的超氧自由基 儿茶酚雌激素代谢产物，将储存在铁蛋白中的Fe3+还原为Fe2+ 它从铁蛋白中释放出来，进而将过氧化氢还原为羟基(Fenton 反应)。这项研究的目标是证明铁是 在雌激素代谢氧化还原循环过程中由铁蛋白动员 它支持羟基自由基生成和DNA损伤 雌激素诱导的致癌。这一假设将通过以下方式检验 铁蛋白/Fe3+氧化还原循环释放Fe2+的研究 雌激素在体外。2.络合Fe~(2+)在 雌激素处理的金黄地鼠肾脏出现前的肾脏 肿瘤，但不是在肝脏中，因为肿瘤不是由这种物质引起的 治疗。3.雌激素对金黄地鼠肾脏Fe2+释放的影响 氧化还原循环依赖的过程(通过使用细胞色素P450抑制剂) 而不是受体介导的过程(通过使用抗雌激素)4. 葛根素对雌激素诱导的仓鼠肾脏肿瘤的影响 雌二醇和含铁量极低、中等或高水平的饮食。

In this project, the role of Fe will be examined in the generation of reactive hydroxy radicals by redox-cycling of estrogens and its role in estrogen-induced carcinogenesis. In westernized societies, excess iron is taken in via dietary supplements. However, an elevated risk of cancer is associated in humans with high body iron stores. The hypothesis is that superoxide radicals, generated by metabolic redox cycling of catecholestrogen metabolites, reduce Fe3+, stored in ferritin, to Fe2+ which is released from ferritin and in turn reduces H2O2 to OH (Fenton reaction). The goal of this study is to demonstrate that iron is mobilized from ferritin during metabolic redox cycling of estrogens and that it supports hydroxy radical generation and DNA damage during estrogen-induced carcinogenesis. This hypothesis will be tested by examining 1. release of Fe2+ from ferritin/Fe3+ by redox cycling of estrogens in vitro. 2. the possible accumulation of chelatable Fe2+ in kidney of estrogen-treated hamsters prior to the appearance of renal tumors, but not in liver in which tumors are not induced by this treatment. 3. Fe2+ release in kidney of estrogen-treated hamsters as a redox cycling-dependent process (by using inhibitors of cytochrome P450) and not a receptor-mediated process (by using antiestrogens) 4. the incidence of estrogen-induced kidney tumors in hamsters treated with estradiol and diets containing very low, medium or high levels of iron.