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Abstract
The gastrointestinal tract is a main route of exposure to polycyclic aromatic hydrocarbons (PAH) due to the ingestion of PAH-contaminated food. Numerous PAH are carcinogenic and most of them are metabolized to biologically active bay- and fjord-region dihydrodiol epoxides that are capable to form stable DNA adducts leading subsequently to mutations and cell transformation. In vitro studies with canine kidney epithelial cells demonstrate that detoxification of dihydrodiol epoxides through glutathione (GSH) conjugate formation catalyzed by glutathione S-transferases and their subsequent removal from the cell by transport proteins of the ATP-binding cassette superfamily is an important process to control DNA adduct levels. In the present study, Caco-2 cells were selected to serve as a model system to investigate both the human intestinal metabolism of the carcinogenic PAH benzo[a]pyrene (BP) and dibenzo[a,l]pyrene (DBP) and transport of their conjugates. In order to allow application of non labeled compounds specific LC-ESI-MS/MS methods were established to determine GSH conjugate formation of the dihydrodiol epoxides of BP and DBP and to demonstrate their efflux from Caco-2 cells.