Bcrp1;Mdr1a/b;Mrp2 combination knockout mice : altered disposition of the dietary carcinogen PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) and its genotoxic metabolites

M.A.J. Vlaming, S.F. Teunissen, E. Steeg, van de, A. Esch, van, E. Wagenaar, L. Brunsveld, T.F.A. Greef, de, H. Rosing, J.H. Schellens, J.H. Beijnen, A.H. Schinkel

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Abstract

The multidrug transporters BCRP, MDR1, MRP2 and MRP3 eliminate toxic compounds from tissues and the body, and affect the pharmacokinetics of many drugs and other potentially toxic compounds. The food-derived carcinogen PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) is transported by BCRP, MDR1 and MRP2. To investigate the overlapping functions of Bcrp1, Mdr1a/b and Mrp2 in vivo, we generated Bcrp1;Mdr1a/b;Mrp2-/- mice, which are viable and fertile. These mice, together with Bcrp1;Mrp2;Mrp3-/- mice, were used to study the effects of the multidrug transporters on the pharmacokinetics of PhIP and its metabolites. 30 minutes after oral or i.v. administration of PhIP (1 mg/kg), PhIP levels in small intestine were 4-6-fold reduced in Bcrp1;Mdr1a/b;Mrp2-/- and Bcrp1;Mrp2;Mrp3-/- mice compared to wild-type mice. Fecal excretion of PhIP was 8-20-fold reduced in knockouts. Biliary PhIP excretion was 41-fold reduced in Bcrp1;Mdr1a/b;Mrp2-/- mice. Biliary and small intestinal levels of PhIP metabolites were reduced in Bcrp1;Mrp2-deficient mice. Furthermore, in both knockout strains kidney levels and urinary excretion of genotoxic PhIP-metabolites were significantly increased, suggesting that reduced biliary excretion of PhIP and PhIP-metabolites leads to increased urinary excretion of these metabolites, and increased systemic exposure. Bcrp1 and Mdr1a limited PhIP brain accumulation. In Bcrp1;Mrp2;Mrp3-/-, but not Bcrp1;Mdr1a/b;Mrp2-/- mice, the carcinogenic metabolites N2-OH-PhIP and PhIP-5-sulphate (a genotoxicity marker) accumulated in liver, indicating that Mrp3 is involved in the sinusoidal secretion of these compounds. We conclude that Bcrp1, Mdr1a/b, Mrp2 and Mrp3 significantly affect tissue disposition and biliary and fecal elimination of PhIP and its carcinogenic metabolites and may affect PhIP-induced carcinogenesis as a result.
Original languageEnglish
Pages (from-to)520-530
Number of pages11
JournalMolecular Pharmacology
Volume85
Issue number3
DOIs
Publication statusPublished - 2014

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