Effect of genistein on the bioavailability and intestinal cancer chemopreventive activity of (-)-epigallocatechin-3-gallate.
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 microM 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 (t(1/2) 148.7 +/- 16.4 versus 111.5 +/- 23.4 min) and exposure (AUC(0-->infinity) 183.9 +/- 20.2 versus 125.8 +/- 26.4 microg/ml x min) of EGCG. Cotreatment with genistein also increased the maximal concentration (C(max)), 6 h exposure (AUC(0-->360 min)), and t(1/2) 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 APC(min/+) 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.
Lambert
Joshua D
JD
Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA. jdl134@psu.edu
Kwon
Seok-Joo
SJ
Ju
Jihyeung
J
Bose
Mousumi
M
Lee
Mao-Jung
MJ
Hong
Jungil
J
Hao
Xingpei
X
Yang
Chung S
CS
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001682:Biological Availability; D002392:Catechin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D004347:Drug Interactions; D019833:Genistein / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D007414:Intestinal Neoplasms / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice
D016588:Anticarcinogenic Agents; D002392:Catechin; C045651:epigallocatechin gallate; D019833:Genistein