Function of multidrug resistance-associated protein 2 in acute hepatic failure rats

Eur J Pharmacol. 2006 Sep 28;546(1-3):152-60. doi: 10.1016/j.ejphar.2006.06.079. Epub 2006 Jul 5.

Abstract

The function of multidrug resistance-associated protein 2 (Mrp2) in the intestine and liver, as well as intestinal Mrp2 expression, was analyzed in CCl(4)-induced acute hepatic failure rats with hyperbilirubinemia. The plasma level of bilirubin glucuronides, endogenous Mrp2-substrates, was 26 microM at 24 h after CCl(4) treatment. Mrp2 protein levels in jejunum decreased to 41% of control level. Mrp2-mediated efflux of 2,4-dinitrophenyl-S-glutathione (DNP-GSH), an Mrp2-substrate, in jejunum decreased to 31% of control in vitro, and was almost completely suppressed in vivo to the same level as that in the presence of probenecid, an Mrp2-inhibitor. Biliary excretion of DNP-GSH was suppressed to the same level as that inhibited by intravenous probenecid. The suppression of Mrp2 and the increased plasma bilirubin glucuronides recovered within 24 h thereafter. These results suggest that hyperbilirubinemia in disease states may be related to the systemic suppression of Mrp2 function.

Publication types

  • Comparative Study

MeSH terms

  • ATP-Binding Cassette Transporters / antagonists & inhibitors
  • ATP-Binding Cassette Transporters / metabolism*
  • Adenosine Triphosphate / metabolism
  • Animals
  • Area Under Curve
  • Bile / metabolism
  • Bilirubin / analogs & derivatives
  • Bilirubin / blood
  • Carbon Tetrachloride
  • Dinitrochlorobenzene / metabolism
  • Glutathione / analogs & derivatives
  • Glutathione / pharmacokinetics
  • Glutathione Transferase / metabolism
  • Hyperbilirubinemia / blood
  • Hyperbilirubinemia / chemically induced
  • Hyperbilirubinemia / metabolism*
  • Hyperbilirubinemia / pathology
  • Ileum / metabolism
  • Intestinal Mucosa / metabolism*
  • Intestines / drug effects
  • Intestines / pathology
  • Jejunum / drug effects
  • Jejunum / metabolism
  • Liver / drug effects
  • Liver / metabolism*
  • Liver / pathology
  • Liver Failure, Acute / blood
  • Liver Failure, Acute / chemically induced
  • Liver Failure, Acute / metabolism*
  • Liver Failure, Acute / pathology
  • Male
  • Organ Size
  • Probenecid / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Time Factors

Substances

  • ATP-Binding Cassette Transporters
  • Abcc2 protein, rat
  • Dinitrochlorobenzene
  • S-(2,4-dinitrophenyl)glutathione
  • bilirubin glucuronate
  • Adenosine Triphosphate
  • Carbon Tetrachloride
  • Glutathione Transferase
  • Glutathione
  • Probenecid
  • Bilirubin