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Involvement of Mrp2 in hepatic and intestinal disposition of dinitrophenyl-S-glutathione in partially hepatectomized rats.
Toxicol Sci. 2005 Mar; 84(1):4-11.TS

Abstract

The ability of the liver and small intestine for secretion of dinitrophenyl-S-glutathione (DNP-SG), a substrate for multidrug resistance-associated protein 2 (Mrp2), into bile and lumen, respectively, as well as expression of Mrp2 in both tissues, were assessed in 70-75% hepatectomized rats. An in vivo perfused intestinal model was used. A single i.v. dose of 30 micromol/kg b.w. of 1-chloro-2,4-dinitrobenzene (CDNB) was administered and its glutathione conjugate, DNP-SG, was determined by HPLC in bile and intestinal perfusate. One and seven days after hepatectomy, biliary excretion of DNP-SG was decreased by 90 and 50% with respect to shams, respectively, when expressed per mass unit. In contrast, intestinal excretion was increased by 63% or unchanged one and seven days post-hepatectomy, respectively. Tissue content of DNP-SG 5 min after CDNB administration was substantially decreased in liver and significantly increased in intestine, one day post-hepatectomy. Western and immunofluorescence studies revealed preserved levels and localization of Mrp2 in both tissues from hepatectomized animals, irrespective of the time analyzed. In spite of preserved expression of Mrp2, the higher availability of DNP-SG in intestinal cells, likely as a consequence of increased glutathione-S-transferase-mediated conjugation of CDNB, may explain the in vivo findings. Further experiments in isolated hepatocytes suggested that decreased synthesis of DNP-SG rather than altered canalicular transport is responsible for the substantial impairment in excretion of this compound into bile. Taken together, these results indicate that the intestine may partially compensate for liver DNP-SG disposition, particularly shortly after surgery, while liver capability is recovering.

Authors+Show Affiliations

Institute of Experimental Physiology, National University of Rosario, S2002LRL-Rosario, Argentina.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15590889

Citation

Villanueva, Silvina S M., et al. "Involvement of Mrp2 in Hepatic and Intestinal Disposition of dinitrophenyl-S-glutathione in Partially Hepatectomized Rats." Toxicological Sciences : an Official Journal of the Society of Toxicology, vol. 84, no. 1, 2005, pp. 4-11.
Villanueva SS, Ruiz ML, Luquita MG, et al. Involvement of Mrp2 in hepatic and intestinal disposition of dinitrophenyl-S-glutathione in partially hepatectomized rats. Toxicol Sci. 2005;84(1):4-11.
Villanueva, S. S., Ruiz, M. L., Luquita, M. G., Sánchez Pozzi, E. J., Catania, V. A., & Mottino, A. D. (2005). Involvement of Mrp2 in hepatic and intestinal disposition of dinitrophenyl-S-glutathione in partially hepatectomized rats. Toxicological Sciences : an Official Journal of the Society of Toxicology, 84(1), 4-11.
Villanueva SS, et al. Involvement of Mrp2 in Hepatic and Intestinal Disposition of dinitrophenyl-S-glutathione in Partially Hepatectomized Rats. Toxicol Sci. 2005;84(1):4-11. PubMed PMID: 15590889.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Involvement of Mrp2 in hepatic and intestinal disposition of dinitrophenyl-S-glutathione in partially hepatectomized rats. AU - Villanueva,Silvina S M, AU - Ruiz,María L, AU - Luquita,Marcelo G, AU - Sánchez Pozzi,Enrique J, AU - Catania,Viviana A, AU - Mottino,Aldo D, Y1 - 2004/12/08/ PY - 2004/12/14/pubmed PY - 2005/6/9/medline PY - 2004/12/14/entrez SP - 4 EP - 11 JF - Toxicological sciences : an official journal of the Society of Toxicology JO - Toxicol Sci VL - 84 IS - 1 N2 - The ability of the liver and small intestine for secretion of dinitrophenyl-S-glutathione (DNP-SG), a substrate for multidrug resistance-associated protein 2 (Mrp2), into bile and lumen, respectively, as well as expression of Mrp2 in both tissues, were assessed in 70-75% hepatectomized rats. An in vivo perfused intestinal model was used. A single i.v. dose of 30 micromol/kg b.w. of 1-chloro-2,4-dinitrobenzene (CDNB) was administered and its glutathione conjugate, DNP-SG, was determined by HPLC in bile and intestinal perfusate. One and seven days after hepatectomy, biliary excretion of DNP-SG was decreased by 90 and 50% with respect to shams, respectively, when expressed per mass unit. In contrast, intestinal excretion was increased by 63% or unchanged one and seven days post-hepatectomy, respectively. Tissue content of DNP-SG 5 min after CDNB administration was substantially decreased in liver and significantly increased in intestine, one day post-hepatectomy. Western and immunofluorescence studies revealed preserved levels and localization of Mrp2 in both tissues from hepatectomized animals, irrespective of the time analyzed. In spite of preserved expression of Mrp2, the higher availability of DNP-SG in intestinal cells, likely as a consequence of increased glutathione-S-transferase-mediated conjugation of CDNB, may explain the in vivo findings. Further experiments in isolated hepatocytes suggested that decreased synthesis of DNP-SG rather than altered canalicular transport is responsible for the substantial impairment in excretion of this compound into bile. Taken together, these results indicate that the intestine may partially compensate for liver DNP-SG disposition, particularly shortly after surgery, while liver capability is recovering. SN - 1096-6080 UR - https://www.unboundmedicine.com/medline/citation/15590889/Involvement_of_Mrp2_in_hepatic_and_intestinal_disposition_of_dinitrophenyl_S_glutathione_in_partially_hepatectomized_rats_ L2 - https://academic.oup.com/toxsci/article-lookup/doi/10.1093/toxsci/kfi053 DB - PRIME DP - Unbound Medicine ER -