Increased bioavailability of the food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in MRP2-deficient rats

MRP2 is an apical transporter expressed in hepatocytes and the epithelial c ells of the small intestine and kidney proximal tubule. It extrudes organic anions, conjugated compounds, and some uncharged amphipaths. We studied th e transport of an abundant food-derived carcinogen, 2-amino-1-methyl-6-phen ylimidazo[4,5-b]pyridine (PhIP) in vitro, using an MRP2 transfected epithel ial cell line (MDCK II) and intestinal explants from Wistar and MRP2-defici ent TR- rats in Ussing chambers. In the experiments with the transfected ce ll line, we could demonstrate more than 3-fold higher transport from basola teral to apical than vice versa, whereas the transport in the parent cell l ine was equal in both directions. These results were confirmed in studies u sing isolated pieces of small intestine from Wistar and TR- rats in the Uss ing chamber. Subsequent in vivo experiments demonstrated that after oral ad ministration, absorption of PhIP was 2-fold higher in the TR- rat than in t he Wistar rat. Consequently, PhIP tissue levels in several organs (liver, k idney, lung, and colon) were 1.7- to 4-fold higher 48 h after oral administ ration. MRP2 mediated transport of unchanged PhIP probably involves intrace llular GSH, because GSH depletion by BSO-treatment in Wistar rats reduced i ntestinal secretion in the Ussing chamber to the same level as in TR- rats. In accordance, BSO treatment increased oral bioavailability in intact Wist ar rats. This study shows for the first time that MRP2-mediated extrusion r educes oral bioavailability of a xenobiotic and protects against an abundan t food-derived carcinogen.