Rapid appearance of hypomethylated DNA in livers of rats fed cancer-promoting, methyl-deficient diets.
Rapid appearance of hypomethylated DNA in livers of rats fed cancer-promoting, methyl-deficient diets.
复制标题
DOI：
--
复制
发表时间：
1989-08
期刊：
影响因子：
11.2
通讯作者：
E. Wainfan;M. Dizik;M. Stender;J. Christman
中科院分区：
文献类型：
--
作者：
E. Wainfan;M. Dizik;M. Stender;J. Christman
长期摄入缺乏甲基来源的饮食会导致大鼠患上肝癌，并促进大鼠和某些品系小鼠的化学致癌。由于调节区胞嘧啶残基的甲基化可以影响基因活性，一些研究人员推测，缺乏甲基的饮食对肿瘤发生的影响是由于细胞无法维持正常的DNA甲基化模式。然而，直到大鼠食用了几个月缺乏甲基的饮食后，肝脏DNA中5-甲基胞嘧啶的含量才有显著下降的报道。为了确定缺乏甲基的饮食是否对核酸甲基化有直接影响，我们通过测量肝细胞DNA和tRNA在体外作为甲基受体的能力，评估了肝细胞DNA和tRNA在体内的甲基化程度。在缺乏蛋氨酸、胆碱、叶酸和维生素B12的饮食中，大鼠在1周内检测到DNA和tRNA的低甲基化，并持续到研究的4周。肝脏DNA合成的显著增加与DNA低甲基化的增加是平行的。由于缺乏甲基的饮食导致肝损伤，新合成的DNA长期不能完全甲基化，这为改变DNA甲基化模式提供了一个可行的机制。我们的结果表明，这样的变化可能发生得足够快，足以在饮食的促癌和在某些情况下诱发癌症的特性中发挥因果作用。
Prolonged intake of diets deficient in sources of methyl groups leads to development of hepatomas in rats and promotes chemical carcinogenesis in both rats and certain strains of mice. Since methylation of cytosine residues in regulatory regions can affect gene activity, several investigators have postulated that the effects of methyl-deficient diets on tumorigenesis result from the inability of cells to maintain normal patterns of DNA methylation. However, significant decreases in the 5-methylcytosine content of liver DNA have not been reported to occur until rats have consumed methyl-deficient diets for several months. To determine whether methyl-deficient diets have immediate effects on nucleic acid methylation, we assessed the degree to which hepatocyte DNA and tRNA were methylated in vivo, by measuring their ability to act as methyl acceptors in vitro. Hypomethylation of DNA and tRNA was detected within 1 week after rats were started on a diet deficient In methionine, choline, folic acid, and vitamin B12 and it persisted throughout the 4 weeks of study. A significant elevation in liver DNA synthesis occurred in parallel with increased hypomethylation of DNA. Chronic failure to fully methylate DNA that is newly synthesized in response to liver damage induced by methyl-deficient diets provides a feasible mechanism for changing patterns of DNA methylation. Our results indicate that such changes could occur rapidly enough to play a causal role in the cancer-promoting and, in some instances, cancer-inducing properties of the diet.