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.
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 intravenous dosing, total excretion of PhIP and its metabolites in bile was > 4-fold reduced in TR(-) rats compared with Wistar rats, while excretion in the 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 but 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 in 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 after ethanol extraction, was elevated by a similar magnitude. Mrp2-mediated transport of the parent compound PhIP is glutathione (GSH)-dependent, because GSH depletion by L-buthionine-[S,R]-sulfoximine (BSO) treatment in Wistar 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 PhIP administration. We conclude that Mrp2 protects against the carcinogen PhIP by biliary excretion of the parent compound and all major phase-II metabolites, but, more importantly, also by direct extrusion of the parent compound from the gut mucosa.
Dietrich
C G
CG
Laboratory for Experimental Hepatology, Department of Gastroenterology and Department of Genetic Metabolic Diseases, Academic Medical Centre, F0-116, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
de Waart
D R
DR
Ottenhoff
R
R
Bootsma
A H
AH
van Gennip
A H
AH
Elferink
R P
RP
D000818:Animals; D001659:Biliary Tract / Q000378:metabolism*; D002273:Carcinogens / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D005260:Female; D007093:Imidazoles / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D007413:Intestinal Mucosa / Q000378:metabolism*; D024101:Mitochondrial Proteins; D051381:Rats; D017208:Rats, Wistar; D012269:Ribosomal Proteins / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins
D002273:Carcinogens; D007093:Imidazoles; C093947:MRP2 protein, S cerevisiae; D024101:Mitochondrial Proteins; D012269:Ribosomal Proteins; D029701:Saccharomyces cerevisiae Proteins; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine