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. ? ? ?
