title: Effect of glucagon-like peptide 2 on hepatic, renal, and intestinal disposition of 1-chloro-2,4-dinitrobenzene.
abstract: The ability of the liver, small intestine, and kidney to synthesize and subsequently eliminate dinitrophenyl-S-glutathione (DNP-SG), a substrate for multidrug resistance-associated protein 2 (Mrp2), was assessed in rats treated with glucagon-like peptide 2 (GLP-2, 12 μg/100 g b.wt. s.c. every 12 h for 5 consecutive days). An in vivo perfused jejunum model with simultaneous bile and urine collection was used. A single intravenous dose of 30 μmol/kg b.wt. 1-chloro-2,4-dinitrobenzene (CDNB) was administered, and its conjugate, DNP-SG, and dinitrophenyl cysteinyl glycine (DNP-CG), resulting from the action of γ-glutamyltransferase on DNP-SG, were determined in bile, intestinal perfusate, and urine by high-performance liquid chromatography. Tissue content of DNP-SG was also assessed in liver, intestine, and kidneys. Biliary excretion of DNP-SG+DNP-CG was decreased in GLP-2 rats with respect to controls. In contrast, their intestinal excretion was substantially increased, whereas urinary elimination was not affected. Western blot and real-time polymerase chain reaction studies revealed preserved levels of Mrp2 protein and mRNA in liver and renal cortex and a significant increase in intestine in response to GLP-2 treatment. Tissue content of DNP-SG detected 5 min after CDNB administration was decreased in liver, increased in intestine, and unchanged in kidney in GLP-2 versus control group, consistent with GLP-2-induced down-regulation of expression of glutathione transferase (GST) Mu in liver and up-regulation of GST-Alpha in intestine at both protein and mRNA levels. In conclusion, GLP-2 induced selective changes in hepatic and intestinal disposition of a common GST and Mrp2 substrate administered systemically that could be of pharmacological or toxicological relevance under therapeutic treatment conditions.
authors.affiliation: Instituto de Fisiología Experimental, Facultad de Ciencias Bioquímicas y Farmacéuticas, Suipacha 570, S2002LRL Rosario, Argentina.
authors.forename: Silvina S M
authors.initials: SS
authors.lastname: Villanueva
authors.forename: Virginia G
authors.initials: VG
authors.lastname: Perdomo
authors.forename: María L
authors.initials: ML
authors.lastname: Ruiz
authors.forename: Juan P
authors.initials: JP
authors.lastname: Rigalli
authors.forename: Agostina
authors.initials: A
authors.lastname: Arias
authors.forename: Marcelo G
authors.initials: MG
authors.lastname: Luquita
authors.forename: Mary
authors.initials: M
authors.lastname: Vore
authors.forename: Viviana A
authors.initials: VA
authors.lastname: Catania
authors.forename: Aldo D
authors.initials: AD
authors.lastname: Mottino
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001646:Bile / Q000378:metabolism; D004136:Dinitrobenzenes / Q000378:metabolism; D004137:Dinitrochlorobenzene / Q000493:pharmacokinetics* / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D053767:Glucagon-Like Peptide 2 / Q000494:pharmacology*; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation / Q000187:drug effects; D005723:gamma-Glutamyltransferase / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D004136:Dinitrobenzenes; D004137:Dinitrochlorobenzene; D053767:Glucagon-Like Peptide 2; D007527:Isoenzymes; D012333:RNA, Messenger; C030190:S-(2,4-dinitrophenyl)glutathione; D005723:gamma-Glutamyltransferase; D005982:Glutathione Transferase; C119995:glutathione S-transferase alpha; D005978:Glutathione