Abstract 5715: Green tea polyphenols implants are more effective than oral dosing in inhibiting benzo[a]pyrene-induced DNA adducts

Abstract

Abstract Green tea is drawing increasing attention due to its potential chemopreventive effect. The polyphenols, including epigallocatechin gallate, epicatechin gallate, epigallocatechin and epicatechin in green tea, are believed to be the active components. However, epidemiological and clinical studies have shown mixed results presumably due to lack of bioavailability when given orally. In this study, polyphenon E, a standardized green tea extract, was administered by novel polycaprolactone implants (two, 2-cm implants; 20% drug load) grafted subcutaneously or by drinking water (0.8% w/v) to female S/D rats. Animals were then challenged with subcutaneous benzo[a]pyrene (BP) implants (2 cm; 10% load), and euthanized after 1 week. Analysis of the lung DNA by 32P-postlabeling showed a significant reduction (50%; p=0.023) in BP-induced DNA adducts in the implant group. A modest (34%) but statistically insignificant adduct reduction was also observed in the drinking water group. The dose of polyphenon E administered by implants was found to be >100 times lower than that by oral route (15.7 mg vs. 1,632 mg). No evidence of toxicity associated with either the polymeric materials or the compounds was found in all these groups based on the body weight and tissue weights. To determine possible mechanisms of action of polyphenon E, we analyzed CYP1A1, CYP1B1 and GST at mRNA and protein expression levels and for the enzyme activities. However, no evidence was found for favorable modulation of these phase I and phase II enzymes by polyphenon E. In in vitro studies, reaction of benzo[a]pyrene-7,8-diol-9,10-epoxide (anti-BPDE) with DNA was found to be strongly inhibited by individual catechins, particularly epigallocatechin gallate, present in polyphenon E, suggesting quenching of the electrophilic metabolite by the catechins. This notion was confirmed by reaction of anti-BPDE with individual catechins by LC/MS/MS. In conclusion, our study demonstrated that i) the effective dose of polyphenon E administered by polymeric implants was over 100-fold lower than the traditional oral route; and ii) polyphenon E exert their chemopreventive effect, at least, in part, due to direct quenching of anti-BPDE (Supported from CA-118114, KLCRP grant and Agnes Brown Duggan Endowment). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5715.