Effects of Quercetin on the detoxification of the food contaminant benzo[ a ]pyrene in the human intestinal Caco-2 cell model

German. Quercetin is a flavonoid that is present in many vegetables, fruits, and beverages. Due to its anti-oxidant, anti-tumor, and anti-inflammatory activity, quercetin has been studied extensively as a chemoprevention agent in several cancer models. Therefore, we investigated the effects of quercetin on the metabolism and excretion of the food contaminant benzo[ a ]pyrene (B[ a ]P) in the gastrointestinal barrier.The human gastrointestinal tract represents the main portal for the entry of xenobiotics including food contaminants and drugs. The epithelium of the small intestine plays an important role in the detoxification of xenobiotics due to the expression of a number of phase I and phase II xenobiotic-metabolizing enzymes (XMEs) as well as several transport proteins of the ATP-binding cassette (ABC) superfamily. In the present study, differentiated human intestinal Caco-2 cells were used as a model for the human small intestine to investigate the metabolism and transport of the pro-carcinogenic food contaminant B[ a ]P.Here, we demonstrate that B[ a ]P phenols are apically excreted by Breast Cancer Resistance Protein (BCRP) as B[ a ]P phase II metabolites including B[ a ]P-glucuronides and B[ a ]P-sulfates. In contrast, the detoxification of the ultimate carcinogenic phase I B[ a ]P metabolite anti -B[ a ]P-7,8-diol-9,10-epoxide (BPDE) can occur only as glutathione conjugate formed by glutathione- S -transferases (GSTs). Transport experiments indicate that these glutathione conjugates of BPDE were excreted overall to the basolateral side of the polarized Caco-2 monolayer. Furthermore, it was shown by induction and inhibition studies that the Multidrug Resistance-associated Proteins (MRPs), but not BCRP, were involved in the transport of the BPDE glutathione conjugates. The transport rates of the detected phase II metabolites of B[ a ]P were increased by pre-treatment with quercetin which stimulated GST, BCRP and MRP1 protein expression. Quercetin increases the apical export of B[ a ]P-glucuronides and B[ a ]P-sulfates by inducing BCRP protein expression and the basolateral excretion of BPDE glutathione conjugates. DNA adduct analysis revealed a protective effect of quercetin. The flavonoid caused a decrease of BPDE-DNA adduct formation up to 85%. In summary, quercetin enhances detoxification of B[ a ]P by inducing the expression of detoxifying enzymes and transport proteins resulting in effective removal of pro-carcinogenic B[ a ]P from intestinal cells.