Interaction of metabolism and transport of toxicological relevant compounds in the gastrointestinal barrier
11/2010-09/2014
This third-party funded project is conducted in the framework of the BfR research program for modern methods in toxicology.
Support code of the DFG: LA 1177/6-1
Homepage of the project: http://gepris.dfg.de/gepris/projekt/156632571
This project, founded by the German Research Foundation is a cooperation between the German Federal Institute for Risk Assessment Department of Food Safety and the Biochemical Institute for Environmental Carcinogens – Prof. Dr. Gernot Grimmer Foundation. The project deals with the analysis of the interaction of metabolism and transport of toxicological relevant compounds in the gastrointestinal barrier.
The interaction of the cytochrome P450 system with the phase II metabolizing enzymes (glutathione S-transferases, UDP-glucuronosyltransferases, and sulfotransferases) as well as the ABC transport proteins represents a possible biochemical barrier against food- and eco-toxicological compounds pointing to an important role in the intestinal mucosa.
In this study it was shown that the resorption of the polycyclic aromatic hydrocarbon benzo[a]pyrene (BP) was affected by an interplay of the phase I enzymes CYP1A1/1B1 , phase II enzymes and the members of the ABC transporter superfamily using the well established in vitro model Caco-2 for the human intestinal barrier. The ABC transporter Breast Cancer Resistance Protein (BCRP) was identified to transport sulfated and glucuronidated BP metabolites. In future studies we are interested in elucidating our in vitro findings in in vivo studies using ABC transporter-knockout mice models (Bcrp-/-). Additionally we want to verify the in vitro identified positive and chemopreventive effects of the flavonoid quercetin in vivo analyzing its influence on the BP toxikokinetic and gene expression of genes involved in the BP-metabolism (CYPs, phase II enzymes, ABC transporter). Finally, the effect on the genotoxicity of BP should be analysed with a special focus on the detoxifying role of the glutathione S-transferases.
The results of this study shall contribute to a better understanding of
- the protective function against toxic and mutagenic compounds in the small intestinal epithelium and
- the targeted influence of chemoprevention by phytochemicals like quercetin
to enhance the intestinal protection against carcinogenic food compounds.