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Hepatic and extrahepatic synthesis and disposition of dinitrophenyl-S-glutathione in bile duct-ligated rats.
Drug Metab Dispos. 2006 Aug; 34(8):1301-9.DM

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 (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 micromol/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 gamma-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 alpha, mu, and pi, 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.

Authors+Show Affiliations

Instituto de Fisiología Experimental, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 570 (S2002LRL)-Rosario, Argentina.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16679389

Citation

Villanueva, Silvina S M., et al. "Hepatic and Extrahepatic Synthesis and Disposition of dinitrophenyl-S-glutathione in Bile Duct-ligated Rats." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 34, no. 8, 2006, pp. 1301-9.
Villanueva SS, Ruiz ML, Soroka CJ, et al. Hepatic and extrahepatic synthesis and disposition of dinitrophenyl-S-glutathione in bile duct-ligated rats. Drug Metab Dispos. 2006;34(8):1301-9.
Villanueva, S. S., Ruiz, M. L., Soroka, C. J., Cai, S. Y., Luquita, M. G., Torres, A. M., Sánchez Pozzi, E. J., Pellegrino, J. M., Boyer, J. L., Catania, V. A., & Mottino, A. D. (2006). Hepatic and extrahepatic synthesis and disposition of dinitrophenyl-S-glutathione in bile duct-ligated rats. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 34(8), 1301-9.
Villanueva SS, et al. Hepatic and Extrahepatic Synthesis and Disposition of dinitrophenyl-S-glutathione in Bile Duct-ligated Rats. Drug Metab Dispos. 2006;34(8):1301-9. PubMed PMID: 16679389.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hepatic and extrahepatic synthesis and disposition of dinitrophenyl-S-glutathione in bile duct-ligated rats. AU - Villanueva,Silvina S M, AU - Ruiz,María L, AU - Soroka,Carol J, AU - Cai,Shi-Ying, AU - Luquita,Marcelo G, AU - Torres,Adriana M, AU - Sánchez Pozzi,Enrique J, AU - Pellegrino,José M, AU - Boyer,James L, AU - Catania,Viviana A, AU - Mottino,Aldo D, Y1 - 2006/05/05/ PY - 2006/5/9/pubmed PY - 2006/10/28/medline PY - 2006/5/9/entrez SP - 1301 EP - 9 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 34 IS - 8 N2 - 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 micromol/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 gamma-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 alpha, mu, and pi, 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. SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/16679389/Hepatic_and_extrahepatic_synthesis_and_disposition_of_dinitrophenyl_S_glutathione_in_bile_duct_ligated_rats_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=16679389 DB - PRIME DP - Unbound Medicine ER -