Tao L, Yang S, Xie M, Kramer P M, Pereira M A
Department of Pathology, Medical College of Ohio, Toledo 43614-5806, USA.
Toxicol Sci. 2000 Apr;54(2):399-407. doi: 10.1093/toxsci/54.2.399.
Trichloroethylene (TCE), dichloroacetic acid (DCA), and trichloroacetic acid (TCA) are environmental contaminants that are carcinogenic in mouse liver. 5-Methylcytosine (5-MeC) in DNA is a mechanism that controls the transcription of mRNA, including the protooncogenes, c-jun and c-myc. We have previously reported that TCE decreased methylation of the c-jun and c-myc genes and increased the level of their mRNAs. Decreased methylation of the protooncogenes could be a result of a deficiency in S-adenosylmethionine (SAM), so that methionine, by increasing the level of SAM, would prevent hypomethylation of the genes. For 5 days, female B6C3F1 mice were administered, daily by oral gavage, either 1000 mg/kg body weight of TCE or 500 mg/kg DCA or TCA. At 30 min after each dose of carcinogen, the mice received, by ip injection, 0-, 30-, 100-, 300-, or 450-mg/kg methionine. Mice were euthanized at 100 min after the last dose of DCA, TCA, or TCE. Decreased methylation in the promoter regions of the c-jun and c-myc genes and increased levels of their mRNA and proteins were found in livers of mice exposed to TCE, DCA, and TCA. Methionine prevented both the decreased methylation and the increased levels of the mRNA and proteins of the two pro-tooncogenes. The prevention by methionine of DCA- TCA-, and TCE-induced DNA hypomethylation supports the hypothesis that these carcinogens act by depleting the availability of SAM. Hence, methionine would prevent DNA hypomethylation by maintaining the level of SAM. Furthermore, the results suggest that the dose of DCA, TCA, or TCE must be sufficient to decrease the level of SAM in order for these carcinogens to be active.
三氯乙烯（TCE）、二氯乙酸（DCA）和三氯乙酸（TCA）是环境污染物，在小鼠肝脏中具有致癌性。DNA中的5-甲基胞嘧啶（5-MeC）是一种控制mRNA转录的机制，包括原癌基因c-jun和c-myc。我们之前报道过，TCE会降低c-jun和c-myc基因的甲基化水平，并增加其mRNA水平。原癌基因甲基化水平降低可能是由于S-腺苷甲硫氨酸（SAM）缺乏所致，因此，蛋氨酸通过提高SAM水平，可以防止基因的低甲基化。雌性B6C3F1小鼠连续5天每天经口灌胃给予1000mg/kg体重的TCE或500mg/kg的DCA或TCA。每次给予致癌物后30分钟，小鼠通过腹腔注射接受0、30、100、300或450mg/kg的蛋氨酸。在最后一次给予DCA、TCA或TCE后100分钟对小鼠实施安乐死。在暴露于TCE、DCA和TCA的小鼠肝脏中，发现c-jun和c-myc基因启动子区域的甲基化降低，其mRNA和蛋白质水平升高。蛋氨酸可防止这两种原癌基因的甲基化降低以及mRNA和蛋白质水平升高。蛋氨酸对DCA、TCA和TCE诱导的DNA低甲基化的预防作用支持了这些致癌物通过消耗SAM的可用性而起作用的假说。因此，蛋氨酸可通过维持SAM水平来防止DNA低甲基化。此外，结果表明，DCA、TCA或TCE的剂量必须足以降低SAM水平，这些致癌物才能发挥作用。
