Folate deficiency alters hepatic and colon MGMT and OGG-1 DNA repair protein expression in rats but has no effect on genome-wide DNA methylation.
Folate deficiency alters hepatic and colon MGMT and OGG-1 DNA repair protein expression in rats but has no effect on genome-wide DNA methylation.
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DOI：
10.1158/1940-6207.capr-09-0231
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发表时间：
2010-01
期刊：
影响因子：
--
通讯作者：
Margison GP
中科院分区：
文献类型：
--
作者：
Duthie SJ;Grant G;Pirie LP;Watson AJ;Margison GP
叶酸缺乏与人类结肠癌有关。研究了给大鼠喂食叶酸缺乏饮食24周对DNA损伤（8-氧代-7，8-二氢鸟嘌呤）、DNA修复（MGMT和OGG-1活性）和表观遗传参数（全基因组胞嘧啶甲基化和细胞甲基化状态指数）的影响。相对于对照饮食，缺乏叶酸的饮食导致血清（约80%; P<0.0001）、全血（约40%; P<0.0001）和组织叶酸水平（取决于取样的组织，在25-60%之间; P<0.05）的水平显著降低，血浆总同型半胱氨酸（约20%; P<0.001）的水平显著升高。35%; P<0.05）和降低的S-腺苷甲硫氨酸至S-腺苷高半胱氨酸浓度（SAM：SAH，约10%）。11%; P<0.05）。肝脏或结肠DNA中5-甲基脱氧胞苷的水平没有显著变化，肝脏DNA胞嘧啶甲基转移酶的活性也没有显著变化。然而，淋巴细胞DNA中的8-氧代-7，8-二氢鸟嘌呤（P<0.001）和DNA修复蛋白OGG 1水平（约为0.001）显著增加。27%; P<0.03）和MGMT（约. 25%;P<0.003），而结肠无明显变化。这可能反映了肝脏（而不是结肠）上调DNA修复酶的能力，以响应DNA损伤升高或核苷酸前体库失衡。这些结果表明，叶酸缺乏可以显着调节DNA损伤和DNA修复提供的机制，它发挥了作用，在人类癌症的病因。我们推测，结肠组织对叶酸缺乏缺乏反应的能力在人类中发生，并可能增加恶性转化的可能性。
Folate deficiency is implicated in human colon cancer. The effects of feeding rats a folate deficient diet for 24 weeks on DNA damage (8-oxo-7,8-dihydroguanine), DNA repair (MGMT and OGG-1 activity) and epigenetic parameters (genome-wide cytosine methylation and indices of cellular methylation status) were investigated. Relative to control diet, the folate-deficient diet resulted in significantly reduced levels of serum (approx 80%; P<0.0001), whole blood (approx 40%; P<0.0001) and tissue folate levels (between 25-60% depending on the tissue sampled; P<0.05), increased plasma total homocysteine (approx. 35%; P<0.05) and decreased S-adenosylmethionine to S-adenosylhomocysteine concentrations (SAM:SAH, approx. 11%; P<0.05). There was no significant change in the levels of 5-methyldeoxycytidine in liver or colon DNA nor in the activity of liver DNA cytosine methyltransferase. However there was a significant increases in 8-oxo-7,8-dihydroguanine (P<0.001) in lymphocyte DNA and in levels of the DNA repair proteins OGG1 (approx. 27%; P<0.03) and MGMT (approx. 25%;P<0.003) in liver, but not in colon. This may reflect the ability of the liver, but not the colon, to upregulate DNA repair enzymes in response either to elevated DNA damage or an imbalance in the nucleotide precursor pool. These results demonstrate that folate deficiency can significantly modulate DNA damage and DNA repair providing mechanisms by which it plays a role in the aetiology of human cancer. We speculate that the inability of colon tissue to respond to folate deficiency occurs in humans and may increase the potential for malignant transformation.