RT Journal Article SR Electronic T1 HEPATIC AND EXTRAHEPATIC SYNTHESIS AND DISPOSITION OF DINITROPHENYL-S-GLUTATHIONE IN BILE DUCT-LIGATED RATS JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 1301 OP 1309 DO 10.1124/dmd.106.009415 VO 34 IS 8 A1 Silvina S. M. Villanueva A1 María L. Ruiz A1 Carol J. Soroka A1 Shi-Ying Cai A1 Marcelo G. Luquita A1 Adriana M. Torres A1 Enrique J. Sánchez Pozzi A1 José M. Pellegrino A1 James L. Boyer A1 Viviana A. Catania A1 Aldo D. Mottino YR 2006 UL http://dmd.aspetjournals.org/content/34/8/1301.abstract AB The ability of the kidney and small intestine to synthesize and subsequently eliminate dinitrophenyl-S-glutathione (DNP-SG), a substrate for the multidrug resistance-associated proteins (Mrps), was assessed in bile duct-ligated (BDL) rats 1, 7, and 14 days after surgery, using an in vivo perfused jejunum model with simultaneous urine collection. A single i.v. dose of 30 μmol/kg b.wt. of 1-chloro-2,4-dinitrobenzene (CDNB) was administered, and its glutathione conjugate DNP-SG and dinitrophenyl cysteinyl glycine derivative, which is the result of γ-glutamyl-transferase action on DNP-SG, were determined in urine and intestinal perfusate by high-performance liquid chromatography. Intestinal excretion of these metabolites was unchanged at day 1, and decreased at days 7 and 14 (–39% and –33%, respectively) after surgery with respect to shams. In contrast, renal excretion was increased by 114%, 150%, and 128% at days 1, 7, and 14. Western blot studies revealed decreased levels of apical Mrp2 in liver and jejunum but increased levels in renal cortex from BDL animals, these changes being maximal between days 7 and 14. Assessment of expression of basolateral Mrp3 at day 14 postsurgery indicated preserved levels in renal cortex, duodenum, jejunum, distal ileum, and colon. Analysis of expression of glutathione-S-transferases α, μ, and π, as well as activity toward CDNB, indicates that formation of DNP-SG was impaired in liver, preserved in intestine, and increased in renal cortex. In conclusion, increased renal tubular conversion of CDNB to DNP-SG followed by subsequent Mrp2-mediated secretion into urine partially compensates for altered liver function in experimental obstructive cholestasis. The American Society for Pharmacology and Experimental Therapeutics