Multidrug resistance-associated protein2 (MRP2) plays an important role in the biliary excretion of glutathione conjugates of 4-hydroxynonenal

Free Radic Biol Med. 2002 Aug 1;33(3):370-8. doi: 10.1016/s0891-5849(02)00906-1.

Abstract

Glutathione (GSH) conjugates of 4-hydroxy-trans-2,3-nonenal (HNE) are the final products of lipid peroxidation. In the present study, the role of multidrug resistance-associated protein 2 (MRP2) in biliary excretion of GSH conjugates of HNE (HNE-SG) was studied in vitro by using Madin-Darby canine kidney II (MDCK II) cells expressing human MRP2 and in vivo using a mutant rat strain whose MRP2 expression is defective (Eisai-hyperbilirubinemic rats [EHBR]). A high-performance liquid chromatography method was developed to assay HNE-SG conjugates. Four diastereomeric HNE-SG conjugates could be separated with this method. Three of four HNE-SG conjugates were detectable after incubation of the cell monolayers with HNE. Expression of human MRP2 resulted in a 10-fold increase in HNE-SG conjugates excretion across the apical membrane of MDCK II cells. The four HNE-SG conjugates appeared swiftly in bile from Sprague Dawley rats after intravenous administration of HNE, whereas no detectable HNE-SG conjugates were observed in the bile of EHBR. These results demonstrate the role of MRP2 in the biliary excretion of HNE-SG conjugates.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehydes / metabolism*
  • Animals
  • Animals, Genetically Modified
  • Bile / metabolism
  • Blotting, Western
  • Cells, Cultured
  • Chromatography, High Pressure Liquid
  • Digestive System / metabolism*
  • Dogs
  • Drug Resistance, Multiple*
  • Glutathione / metabolism*
  • Humans
  • In Vitro Techniques
  • Kidney / metabolism
  • Lipid Peroxidation
  • Male
  • Membrane Transport Proteins*
  • Multidrug Resistance-Associated Proteins / physiology*
  • Protein Binding
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Aldehydes
  • Membrane Transport Proteins
  • Multidrug Resistance-Associated Proteins
  • multidrug resistance-associated protein 2
  • Glutathione
  • 4-hydroxy-2-nonenal
  • multidrug resistance-associated protein 1