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First published on May 5, 2006; DOI: 10.1124/dmd.106.009415

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Received for publication January 19, 2006.
Revised May 2, 2006.
Accepted for publication May 3, 2006.

Hepatic and extrahepatic synthesis and disposition of dinitrophenyl-S-glutathione in bile duct ligated rats

Silvina S.M. Villanueva 1, Maria L. Ruiz 1, Carol J. Soroka 2, Shi-Ying Cai 2, Marcelo G. Luquita 1, Adriana M. Torres 3, Enrique J. Sanchez Pozzi 1, Jose M. Pellegrino 1, James L. Boyer 2, Viviana A. Catania 1, Aldo D. Mottino 1*

1 Instituto de Fisiologia Experimental, Universidad Nacional de Rosario 2 Liver Center and Department of Internal Medicine, Yale University School of Medicine 3 Farmacologia, Facultad de Cs Bioq y Farm, Universidad Nacional de Rosario

* Address correspondence to: E-mail: amottino{at}unr.edu.ar

Abstract

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 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.w. of 1-chloro-2,4-dinitrobenzene (CDNB) was administered and its glutathione conjugate DNP-SG and dinitrophenyl cysteinyl glycine (DNP-CG) derivative, which is the result of {gamma}-glutamyl-transferase action on DNP-SG, were determined in urine and intestinal perfusate by HPLC. 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 post-surgery indicated preserved levels in renal cortex, duodenum, jejunum, distal ileum and colon. Analysis of expression of glutathione-S-transferases alpha, mu and pi, as well as activity towards 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.


Key words: ABC transporters, glutathione, glutathione transferases, hepatobiliary transport, intestinal transport, liver disease, MRP, renal elimination, toxicity


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