Oxidative mutagenesis:Iron, Ascorbic Acid and Genes

氧化诱变：铁、抗坏血酸和基因

• 批准号: 6447620
• 负责人: CHRISTOPHER L. BOWLUS
• 金额: $ 7.4万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-15 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6447620
• 关键词: DNA damage; SCID mouse; adduct; antioxidants; ascorbate; atomic absorption spectrometry; dietary iron; dietary supplements; electrospray ionization mass spectrometry; gastrointestinal absorption /transport; gel mobility shift assay; gene expression; gene mutation; genotype; hepatocellular carcinoma; hereditary hemochromatosis; iron storage disorder; laboratory mouse; lipid metabolism; lipid peroxides; membrane transport proteins; nutrient interaction; nutrition related neoplasm /cancer; nutrition related tag; oxidative stress; p53 gene /protein; single strand conformation polymorphism; tumor promoters

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.

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。 能通过芬顿化学产生羟基自由基的氧化剂。抗坏血酸 酸是一种非常有效的羟基自由基清除剂，可以提高饮食，非 通过增加通过根尖的铁转移来增加血红素铁的吸收 肠上皮细胞膜。在铁存在的情况下，在体外 实验表明，抗坏血酸起到了促氧化剂的作用。是否 抗坏血酸在体内是否具有促氧化活性仍在争论中。 遗传性血色沉着症是一种常见的常染色体隐性遗传病。 其中对肠道铁吸收的调节失去了。由此产生的 铁超载与过度的脂质过氧化有关。的模式 HH中的P53突变与DNA的诱变潜力一致 加合物，L，N6-亚乙基脱氧腺苷。 研究人员推测，尽管肠道的正常调节 铁的吸收，抗坏血酸和铁的补充将导致 足够的铁超载会增加脂质过氧化和EDA的形成。 此外，在HH中同时补充铁和抗坏血酸，其中 肠道铁的吸收失去调节，会导致病情恶化 铁超载导致更大的脂质过氧化，EDA的形成和 肝细胞癌。 研究人员提出的实验是为了检查 膳食铁与抗坏血酸、遗传铁的交互作用 铁负荷过重、脂质过氧化和致突变。他们将使用一个 易形成肝细胞的HH小鼠模型。