Carcinogenesis Advance Access originally published online on August 5, 2008
Carcinogenesis 2008 29(10):2019-2024; 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, Piscataway, NJ 08854, USA
2 Division of Food Science, College of Natural Science, Seoul Women’s University, Seoul 139-774, Korea
3 Present address: Department of Food Science, The Pennsylvania State University, 332 Food Science Building, University Park, PA 16802, USA
* To whom correspondence should be addressed. Tel: +1 814 865 5223; Fax: +1 814 863 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 cotreatment of HT-29 human colon cancer cells with genistein (from soy) increased cytosolic EGCG by 2- to 5-fold compared with 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 coadministration 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 versus 111.5 ± 23.4 min) and exposure (AUC0
183.9 ± 20.2 versus 125.8 ± 26.4 µg/ml x min) of EGCG. Cotreatment with genistein also increased the maximal concentration (Cmax), 6 h exposure (AUC0360 min), and t1/2 of EGCG in the small intestine by 2.0-, 4.7- and 1.4-fold, respectively, compared with 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 adenomatous polyposis coli (APC)min/+ mice. This combination increased the multiplicity of tumors in the medial and distal small intestine: the largest increase was in tumors >2 mm in diameter (4.3-fold compared with 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.
Abbreviations: APC, adenomatous polyposis coli; DMSO, dimethyl sulfoxide; EGCG, (-)-epigallocatechin-3-gallate; i.g., intragastric; MRP, multidrug resistance-related protein; t1/2, half-life
Received July 7, 2008; revised July 28, 2008; accepted August 1, 2008.