Carcinogenesis Advance Access published online on August 5, 2008
Carcinogenesis, doi:10.1093/carcin/bgn182
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Effect of genistein on the bioavailability and intestinal cancer chemopreventive activity of (-)-epigallocatechin-3-gallate
1 Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 08854
3 Division of Food Science, College of Natural Science, Seoul Women's University, Seoul, Korea, 139-774
* To whom correspondence and requests for reprints should be addressed: Joshua D. Lambert, Ph.D., Department of Food Science, The Pennsylvania State University, 332 Food Science Building, University Park, PA 16802, Tel: (814)865-5223; FAX (814)865-6132. Email: jdl134{at}psu.edu
The green tea (Camellia sinensis) catechin, (-)-epigallocatechin-3-gallate (EGCG), has shown cancer preventive activity in animal models. Previously, we have reported the bioavailability of EGCG in rats and mice. Here, we report that co-treatment of HT-29 human colon cancer cells with genistein (from soy) increased cytosolic EGCG by 2 – 5-fold compared to treatment with EGCG only. Inclusion of genistein, at non-cytotoxic concentrations, increased the growth inhibitory effects of EGCG against HT-29 cells (up to 2-fold at 20 µM genistein). Intragastric co-administration of EGCG (75 mg/kg) and genistein (200 mg/kg) to CF-1 mice resulted in an increase in plasma half-life (t1/2 148.7±16.4 vs. 111.5±23.4 min) and exposure (AUC0
183.9±20.2 vs. 125.8±26.4 µg/mL x min) of EGCG. Co-treatment with genistein also increased the maximal concentration (Cmax), AUC0360min, and t1/2 of EGCG in the small intestine by 2.0-, 4.7-, and 1.4-fold, respectively, compared to mice treated with EGCG only. Contrary to our expectations, the combination of 0.01% EGCG in the drinking fluid and 0.2% genistein in the diet enhanced intestinal tumorigenesis in male APCmin/+ mice. This combination increased the multiplicity of tumors in the medial and distal small intestine: the largest increase was in tumors greater than 2 mm in diameter (4.3-fold compared to controls). This study demonstrates that although genistein can enhance EGCG bioavailability and in vitro growth inhibitory activity, this combination enhances tumorigenesis in the APCmin/+ mouse. These results further show the need for careful cancer prevention studies in animal models and for caution when interpreting data from in vitro studies.
Key Words: (-)-epigallocatechin-3-gallate • genistein • Camellia sinensis • Glycine max • cancer prevention
2 Present Address: Department of Food Science, The Pennsylvania State University, 332 Food Science Building, University Park, PA 16802, Tel: (814)865-5223; FAX (814)865-6132. Email: jdl134{at}psu.edu
Received July 7, 2008; revised July 28, 2008; accepted August 1, 2008.