Oxidative mutagenesis:Iron, Ascorbic Acid and Genes

描述（由申请人提供） 铁是许多细胞功能所必需的，但它也是一种强有力的促进剂。 通过芬顿化学作用产生羟基自由基的氧化剂。 抗坏血 酸，一种非常有效的羟基自由基清除剂，可以提高饮食，非- 血红素铁吸收通过增加铁的转移跨越顶端 肠上皮细胞膜。 在铁的存在下，在体外 实验表明抗坏血酸起促氧化剂的作用。 是否 抗坏血酸在体内是否具有促氧化活性仍在争论。 遗传性血色病是一种常见的常染色体隐性遗传病， 从而失去对肠铁吸收的调节。 所得 铁超负荷与过度脂质过氧化有关。 的格局 HH中的p53突变与DNA的致突变潜力一致 加合物，1，N6-乙烯脱氧腺苷。 研究人员假设，尽管肠道的正常调节， 铁吸收，抗坏血酸和铁补充剂将导致 足够的铁过载增加脂质过氧化和EdA形成。 此外，在HH中共同补充铁和抗坏血酸，其中 肠道铁吸收的调节失去，将导致恶化， 铁超载导致更大的脂质过氧化，EdA形成， 肝细胞癌 研究人员提出了一些实验，旨在检查 膳食铁和抗坏血酸与遗传铁的交互作用 铁负荷超负荷、脂质过氧化和致突变。 他们将使用一个 HH的小鼠模型，其倾向于肝细胞形成。

DESCRIPTION (provided by applicant) Iron is essential for many cellular functions, but it is also a potent pro- oxidant that can produce hydroxyl radicals through Fenton chemistry. Ascorbic acid, a very potent scavenger of hydroxyl radicals, can enhance dietary, non- heme iron absorption by increasing the transfer of iron across the apical membrane of intestinal epithelial cells. In the presence of iron, in vitro experiments have shown ascorbic acid to act as a pro-oxidant. Whether ascorbic acid has pro-oxidant activity in vivo continues to be debated. Hereditary hemochromatosis (HH) is a common autosomal recessive disease in which the regulation of intestinal iron absorption is lost. The resulting iron overload is associated with excessive lipid peroxidation. The pattern of p53 mutations in HH is consistent with the mutagenic potential of the DNA adduct, l,N6-ethenodeoxyadenosine. The investigators hypothesize that despite the normal regulation of intestinal iron absorption, ascorbic acid and iron supplementation will lead to sufficient iron overload to increase lipid peroxidation and EdA formation. Furthermore, co-supplementation with iron and ascorbic acid in HH, in which regulation of intestinal iron absorption is lost, will result in worsening the iron overload leading to greater lipid peroxidation, EdA formation and hepatocellular carcinoma. The investigators propose experiments that are designed to examine the interactive effects of dietary iron and ascorbic acid and genetic iron overload on iron loading, lipid peroxidation and mutagenesis. They will use a mouse model of HH that is prone to hepatocellular formation.