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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
1R03CA125780-01
Application #
7214443
Study Section
Special Emphasis Panel (ZCA1-SRRB-F (O1))
Program Officer
Steele, Vernon E
Project Start
2006-09-20
Project End
2008-08-31
Budget Start
2006-09-20
Budget End
2007-08-31
Support Year
1
Fiscal Year
2006
Total Cost
$77,041
Indirect Cost
Name
Rutgers University
Department
Biology
Type
Schools of Pharmacy
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Lambert, Joshua D; Kennett, Mary J; Sang, Shengmin et al. (2010) Hepatotoxicity of high oral dose (-)-epigallocatechin-3-gallate in mice. Food Chem Toxicol 48:409-16
Lambert, Joshua D; Lu, Gang; Lee, Mao-Jung et al. (2009) Inhibition of lung cancer growth in mice by dietary mixed tocopherols. Mol Nutr Food Res 53:1030-5
Bose, Mousumi; Lambert, Joshua D; Ju, Jihyeung et al. (2008) The major green tea polyphenol, (-)-epigallocatechin-3-gallate, inhibits obesity, metabolic syndrome, and fatty liver disease in high-fat-fed mice. J Nutr 138:1677-83
Yang, Chung S; Sang, Shengmin; Lambert, Joshua D et al. (2008) Bioavailability issues in studying the health effects of plant polyphenolic compounds. Mol Nutr Food Res 52 Suppl 1:S139-51
Lambert, Joshua D; Kwon, Seok-Joo; Ju, Jihyeung et al. (2008) Effect of genistein on the bioavailability and intestinal cancer chemopreventive activity of (-)-epigallocatechin-3-gallate. Carcinogenesis 29:2019-24
Lambert, Joshua D; Sang, Shengmin; Yang, Chung S (2008) N-Acetylcysteine enhances the lung cancer inhibitory effect of epigallocatechin-3-gallate and forms a new adduct. Free Radic Biol Med 44:1069-74
Lambert, Joshua D; Sang, Shengmin; Yang, Chung S (2007) Biotransformation of green tea polyphenols and the biological activities of those metabolites. Mol Pharm 4:819-25