Dietary folate and selenium affect dimethylhydrazine-induced aberrant crypt formation, global DNA methylation and one-carbon metabolism in rats
Dietary folate and selenium affect dimethylhydrazine-induced aberrant crypt formation, global DNA methylation and one-carbon metabolism in rats
复制标题
DOI：
10.1093/jn/133.9.2907
复制
发表时间：
2003-09-01
影响因子：
4.2
通讯作者：
Uthus, EO
中科院分区：
文献类型：
--
作者：
Davis, CD;Uthus, EO
一些观察结果表明DNA甲基化在癌症发病机制中的作用。虽然硒和叶酸缺乏都已被证明会导致整体DNA低甲基化和增加癌症易感性，但这两种营养素对单碳代谢的影响不同。因此，本研究的目的是研究膳食硒和叶酸的相互作用。在2 × 2因子设计中，断奶大鼠fisher -344 （n = 23/日粮）分别饲喂含0或2.0 mg硒（亚硒酸盐）/kg和0或2.0 mg叶酸/kg的日粮。12周实验第3、4周时，19只大鼠/日粮腹腔注射二甲肼（DMH, 25 mg/kg）， 4只大鼠/日粮腹腔注射生理盐水。硒缺乏降低了结肠DNA甲基化、肝脏DNA甲基转移酶和甜菜碱同型半胱氨酸甲基转移酶活性（P < 0.05），升高了血浆谷胱甘肽浓度。叶酸缺乏增加了异常隐窝/异常隐窝数量（P < 0.05）、结肠s -腺苷型同型半胱氨酸浓度和肝脏胱硫氨酸合成酶活性（P < 0.05）。硒和叶酸相互作用（P < 0.0001）影响单碳代谢和癌症易感性，在叶酸缺乏和补充硒的大鼠中，异常隐窝数量、血浆同型半胱氨酸和肝脏s -腺苷型半胱氨酸浓度最高，血浆叶酸和肝脏s -腺苷型蛋氨酸浓度和肝脏蛋氨酸合成酶活性最低。这些结果表明，硒剥夺可以改善叶酸缺乏的一些影响，可能是通过将同型半胱氨酸（叶酸缺乏的结果）的积累分流到谷胱甘肽。
Several observations suggest a role for DNA methylation in cancer pathogenesis. Although both selenium and folate deficiency have been shown to cause global DNA hypomethylation and increased cancer susceptibility, the nutrients have different effects on one-carbon metabolism. Thus, the purpose of this study was to investigate the interactive effects of dietary selenium and folate. Weanling, Fischer-344 rats (n = 23/diet) were fed diets containing 0 or 2.0 mg selenium (as selenite)/kg and 0 or 2.0 mg folate/kg in a 2 X 2 factorial design. After 3 and 4 wk of a 12-wk experiment, 19 rats/diet were injected intraperitoneally with dimethylhydrazine (DMH, 25 mg/kg) and 4 rats/diet were administered saline. Selenium deficiency decreased (P < 0.05) colonic DNA methylation and the activities of liver DNA methyltransferase and betaine homocysteine methyltransferase and increased plasma glutathione concentrations. Folate deficiency increased (P < 0.05) the number of aberrant crypts per aberrant crypt foci, the concentration of colonic S-adenosylhomocysteine and the activity of liver cystathionine synthase. Selenium and folate interacted (P < 0.0001) to influence one-carbon metabolism and cancer susceptibility such that the number of aberrant crypts and the concentrations of plasma homocysteine and liver S-adenosylhomocysteine were the highest and the concentrations of plasma folate and liver S-adenosylmethionine and the activity of liver methionine synthase were the lowest in rats fed folate-deficient diets and supplemental selenium. These results suggest that selenium deprivation ameliorates some of the effects of folate deficiency, probably by shunting the buildup of homocysteine (as a result of folate deficiency) to glutathione.