Lack of evidence for green tea polyphenols as DNA methylation inhibitors in murine prostate.
Lack of evidence for green tea polyphenols as DNA methylation inhibitors in murine prostate.
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DOI：
10.1158/1940-6207.capr-09-0010
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发表时间：
2009-12
期刊：
影响因子：
--
通讯作者：
Karpf AR
中科院分区：
文献类型：
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作者：
Morey Kinney SR;Zhang W;Pascual M;Greally JM;Gillard BM;Karasik E;Foster BA;Karpf AR
据报道，绿茶多酚（GTPs）在培养细胞中可抑制DNA甲基化。在此我们利用小鼠测试了口服GTPs是否会在体内影响正常或癌症特异性DNA甲基化。从4周龄开始，给野生型（WT）和小鼠前列腺转基因腺癌（TRAMP）小鼠在饮用水中添加0.3%的GTPs。为了监测DNA甲基化，我们测量了5 - 甲基 - 脱氧胞苷（5mdC）水平、B1重复元件的甲基化以及Mage - a8基因的甲基化。在12周和24周龄的野生型小鼠的前列腺、肠道和肝脏中，这些参数中的每一个都没有变化，唯一的例外是12周时肝脏中的5mdC有所下降。在经GTP处理的TRAMP小鼠中，在12周或24周时，TRAMP小鼠前列腺中的5mdC水平以及肿瘤进展过程中四个高甲基化位点的甲基化状态没有改变。非常令人惊讶的是，尽管已知的GTPs药效学标志物在野生型和TRAMP小鼠的前列腺中都发生了改变，但GTP处理并没有抑制TRAMP小鼠的肿瘤进展。我们还分别给TRAMP小鼠施用0.1%、0.3%或0.6%的GTPs，持续12周，并测量了前列腺、肠道和肝脏组织中5mdC水平以及B1和Mage - a8的甲基化。没有观察到DNA甲基化状态的剂量依赖性改变。使用HELP分析进行的全基因组DNA甲基化图谱分析也显示GTP没有显著的去甲基化作用。这些数据表明，口服GTPs不会影响小鼠前列腺中正常或癌症特异性DNA甲基化。
Green tea polyphenols (GTPs) have been reported to inhibit DNA methylation in cultured cells. Here we tested whether oral consumption of GTPs affects normal or cancer specific DNA methylation in vivo, using mice. Wildtype (WT) and Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice were administered 0.3% GTPs in drinking water beginning at 4 weeks of age. To monitor DNA methylation, we measured 5-methyl-deoxycytidine (5mdC) levels, methylation of the B1 repetitive element, and methylation of the Mage-a8 gene. Each of these parameters were unchanged in prostate, gut, and liver from WT mice at both 12 and 24 weeks of age, with the single exception of a decrease of 5mdC in the liver at 12 weeks. In GTP-treated TRAMP mice, 5mdC levels and the methylation status of four loci hypermethylated during tumor progression were unaltered in TRAMP prostates at 12 or 24 weeks. Quite surprisingly, GTP treatment did not inhibit tumor progression in TRAMP mice, although known pharmacodynamic markers of GTPs were altered in both WT and TRAMP prostates. We also administered 0.1%, 0.3%, or 0.6% GTPs to TRAMP mice for 12 weeks and measured 5mdC levels and methylation of B1 and Mage-a8 in prostate, gut, and liver tissues. No dose-dependent alterations in DNA methylation status were observed. Genome-wide DNA methylation profiling using the HELP assay also revealed no significant hypomethylating effect of GTP. These data indicate that oral administration of GTPs does not affect normal or cancer-specific DNA methylation in the murine prostate.