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 μ/100 g b.w., 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 i.v. dose of 30 μmol/kg b.w. of 1-chloro-2,4-dinitrobenzene (CDNB) was administered, and its conjugate DNP-SG, as well as dinitrophenyl cysteinyl glycine (DNP-CG), resulting from the action of γ-glutamyl-transferase 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 PCR 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 vs. control group, consistent with GLP-2-induced down-regulation of expression of GSTµ in liver and up-regulation of GSTμ 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.