Role of methylation in prevention the toxicity of epigallocatechin-3-gallate

甲基化在预防表没食子儿茶素-3-没食子酸酯毒性中的作用

• 批准号: 7214443
• 负责人: JOSHUA D LAMBERT
• 金额: $ 7.7万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-20 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7214443
• 关键词: cancer prevention; carbon; catechols; fluid; glutathione; human; metabolism; methylation; methyltransferase; oxidative stress; prevention; role; serum; tea

DESCRIPTION (provided by applicant): Green tea (Camellia sinensis) and its major polyphenolic constituent, (-)-epigallocatechin-3-gallate (EGCG) have been suggested to have numerous beneficial health benefits including prevention of cancer and heart disease. A recent epidemiological study of breast cancer risk in Asian-American women found that green tea consumption was correlated with reduced risk of breast cancer development in women with at least one low activity allele of catechol-O-methyltransferase (COMT). Methylation of EGCG has been shown to play a major role in its phase II metabolism. Although consumption of green tea has generally been regarded as safe, recent studies in rodents, dogs, and case-reports of humans have suggested that consumption of high doses of green tea-derived supplements can results in intestinal and hepatic toxicity, as well as death. Based on these data, we hypothesize that COMT-mediated methylation of EGCG serves as a protective mechanism against EGCG- induced oxidative stress and hepatotoxicity. Polymorphisms or drug-interactions which reduce this methylation would increase sensitivity to these toxic effects. We will test this hypothesis using the following specific aims: 1. To determine the effect of COMT inhibition or deficiency on EGCG-induced oxidative stress and hepatotoxicity in the mouse. 2. To determine the effect of COMT inhibition on the metabolic profile of EGCG and on EGCG-induced changes in serum and tissue markers of glutathione and one carbon metabolism in the mouse will also be determined. Successful completion of the proposed research will enhance our understanding of the potential toxicity of high doses of EGCG and the involved mechanisms. Further, it will provide insight into the protective role of COMT and help us to identify populations, some of which may be enrolled in cancer prevention intervention trials that are potentially at risk for EGCG intoxication. Finally, methodologies developed during this proposal will be useful in monitoring safety in human intervention studies of EGCG.

描述（由申请人提供）：绿茶（Camellia sinensis）及其主要的多酚组成部分，（ - ） - epigallocatechin-3-gallate（EGCG）（EGCG）具有许多有益的健康益处，包括预防癌症和心脏病。最近在亚裔妇女乳腺癌风险的流行病学研究发现，绿茶的消费量与至少有一个低活性等位基因的Catechol-O-O-甲基转移酶（COMT）的妇女的乳腺癌发展风险降低相关。 EGCG的甲基化已显示在其II期代谢中起主要作用。尽管通常认为绿茶的消费被认为是安全的，但对人类的啮齿动物，狗和病例报告的最新研究表明，高剂量的绿茶衍生的补充剂的消费可以导致肠道和肝毒性以及死亡。基于这些数据，我们假设COMT介导的EGCG甲基化是针对EGCG诱导的氧化应激和肝毒性的保护机制。减少这种甲基化的多态性或药物互动将增加对这些毒性作用的敏感性。我们将使用以下特定目的检验该假设：1。确定COMT抑制或缺乏对EGCG诱导的小鼠氧化应激和肝毒性的影响。 2。为了确定COMT抑制对EGCG代谢特征的影响以及EGCG诱导的谷胱甘肽血清和组织标记变化以及小鼠中一种碳代谢的变化。成功完成拟议的研究将增强我们对高剂量EGCG和所涉及机制的潜在毒性的理解。此外，它将提供有关COMT保护作用的洞察力，并帮助我们确定人群，其中一些人可能会参与预防癌症干预试验，这些试验可能有可能有EGCG中毒的风险。最后，在本提案中开发的方法将有助于监测EGCG人类干预研究的安全性。