TY - JOUR
T1 - 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
AU - Vlaming, M.A.J.
AU - Teunissen, S.F.
AU - Steeg, van de, E.
AU - Esch, van, A.
AU - Wagenaar, E.
AU - Brunsveld, L.
AU - Greef, de, T.F.A.
AU - Rosing, H.
AU - Schellens, J.H.
AU - Beijnen, J.H.
AU - Schinkel, A.H.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
U2 - 10.1124/mol.113.088823
DO - 10.1124/mol.113.088823
M3 - Article
C2 - 24334255
SN - 1421-0111
VL - 85
SP - 520
EP - 530
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 3
ER -