Mrp2-deficiency in the rat impairs biliary and intestinal excretion and influences metabolism and disposition of the food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)

While metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the most abundant food-derived heterocyclic amine and carcinogen, has been studied extensively in several species, transport of this compound and its metabolites has not been defined yet. Therefore we studied metabolism and disposition of PhIP in Wistar and Mrp2-deficient TR- rats to determine the role of Mrp2 in the defence against this compound. In the first 2 h after i ntravenous dosing, total excretion of PhIP and its metabolites in bile was >4-fold reduced in TR- rats compared with Wistar rats, while excretion in t he urine of the TR- rat was 1.8-fold higher. This difference was the result of an almost complete absence of secretion of glucuronidated metabolites b ut also a reduced level of secretion of unchanged PhIP into bile of the TR- rat. Direct intestinal excretion of unmetabolized PhIP was 3-fold higher i n Wistar versus TR- rats. As a consequence, PhIP tissue levels in the liver were 1.7-fold higher in TR- rats, and tissue binding of PhIP, determined a fter ethanol extraction, was elevated by a similar magnitude. Mrp2-mediated transport of the parent compound PhIP is glutathione (GSH)-dependent, beca use GSH depletion by L-buthionine[S,R]-sulfoximine (BSO) treatment in Wista r rats reduced intestinal secretion to the same level as that in TR- rats. TR- rats produced less glucuronides and 4'-OH-PhIP in the 2 h following PhI P administration, We conclude that Mrp2 protects against the carcinogen PhI P by biliary excretion of the parent compound and all major phase-II metabo lites, but, more importantly, also by direct extrusion of the parent compou nd from the gut mucosa.