DIET-INDUCED DNA DAMAGE AND ALTERED NUCLEOTIDE-METABOLISM IN LYMPHOCYTES FROM METHYL-DONOR-DEFICIENT RATS
DIET-INDUCED DNA DAMAGE AND ALTERED NUCLEOTIDE-METABOLISM IN LYMPHOCYTES FROM METHYL-DONOR-DEFICIENT RATS
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DOI：
10.1093/carcin/10.7.1209
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发表时间：
1989-07-01
期刊：
影响因子：
4.7
通讯作者：
YIN, L
中科院分区：
文献类型：
--
作者：
JAMES, SJ;YIN, L
长期喂食甲基供体缺乏饮食的肿瘤诱导已经得到很好的建立，然而，在这种模型中易于发生肿瘤的生化和分子机制仍然没有很好的理解。本研究的目的是评估DNA损伤和改变的核苷酸代谢的淋巴细胞从Fischer 344大鼠喂养的四个半纯化的饮食之一：（i）缺乏蛋氨酸和胆碱;（ii）缺乏叶酸;（iii）缺乏蛋氨酸，胆碱和叶酸;或（iv）补充对照饮食。DNA链断裂的积累，评估DNA解旋在碱中，从蛋氨酸/胆碱缺乏和叶酸缺乏组的淋巴细胞中增加，但在所有三个甲基捐助者缺乏组中是最严重的。淋巴细胞DNA损伤始终与叶酸依赖性胸苷酸合成的改变以及DNA修复相关的吡啶核苷酸、烟酰胺腺嘌呤二核苷酸的细胞内水平降低相关。在肝脏中，观察到叶酸缺乏和甲硫氨酸/胆碱缺乏之间的协同亲脂相互作用，证实了这些营养素之间的代谢相互关系。两者合计，结果表明，叶酸缺乏症与蛋氨酸/胆碱缺乏症相互作用，以加强甲基供体缺乏症的症状，叶酸依赖性胸苷酸合成的改变与淋巴细胞中的DNA损伤有关。这些代谢异常可能导致免疫功能障碍与慢性喂养甲基供体缺乏的饮食。
Tumor induction with chronic feeding of methyl-donor-deficient diets has been well established; however, the biochemical and molecular mechanisms which predipose to tumorigenesis in this model are still not well understood. The purpose of the present investigation was to assess DNA damage and altered nucleotide metabolism in lymphocytes from Fischer 344 rats fed one of four semi-purified diets: (i) deficient in methionine and choline; (ii) deficient in folic acid; (iii) deficient in methionine, choline and folic acid; or (iv) a supplemented control diet. The accumulation of DNA-strand breaks, as assessed by DNA unwinding in alkali, was increased in lymphocytes from both the methionine/choline-deficient and folate-deficient groups, but was most severe in the group deficient in all three methyl donors. Lymphocyte DNA damage was consistently associated with alterations in folate-dependent thymidylate synthesis, and a decrease in intracellular levels of the DNA-repair-associated pyridine nucleotide, nicotinamide adenine dinucleotide. In the liver, a synergistic lipotropic interaction between folate deficiency and methionine/choline deficiency was observed, confirming the metabolic inter-relationship between these nutrients. Taken together, the results suggest that folate deficiency interacts with methionine/choline deficiency to potentiate symptoms of methyl-donor deficiency and that alterations in folate-dependent thymidylate synthesis are related to DNA damage in lymphocytes. These metabolic aberrations may contribute to immune dysfunction with chronic feeding of methyl-donor-deficient diets.