Format

Send to

Choose Destination
See comment in PubMed Commons below
Arch Biochem Biophys. 2003 Mar 15;411(2):243-50.

Characterization of multidrug resistance-associated protein 2 in the hepatocellular disposition of 4-hydroxynonenal.

Author information

  • 1Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, CO 80262, USA.

Abstract

4-hydroxynonenal (4HNE) is a major product of peroxidative membrane lipid destruction and exerts a variety of deleterious actions through formation of covalent adducts with cellular nucleophiles. Consequently, a number of cellular enzyme systems exist that are capable of detoxifying this reactive aldehyde by oxidation, reduction, or conjugation with glutathione. In this investigation we characterize the multidrug resistance-associated protein 2 (MRP2) as the primary transmembrane transport protein in hepatocytes responsible for extracellular export of 4HNE-glutathione conjugate (HNE-SG) from the intracellular site of its formation. Suspensions of freshly isolated hepatocytes (10(6) cells/ml) prepared from either wild-type (WT) Wistar rats or TR(-) rats possessing a mutated Mrp2 gene were incubated with 4HNE (50 nmol/10(6) cells). The formation of 4HNE metabolites, 4-hydroxynonenoic acid (HNA) and HNE-SG, was quantified in the intracellular and extracellular fractions. These studies demonstrated that freshly isolated hepatocytes from both WT and TR(-) rats formed and exported the oxidized metabolite (HNA) to similar extents. Likewise, both populations of hepatocytes displayed nearly identical rates of glutathione conjugation with 4HNE. However, the rate of HNE-SG export from TR(-) hepatocytes was approximately fourfold less than that of WT hepatocytes. In TR(-) hepatocytes, HNE-SG accumulated and remained predominantly intracellular throughout the time course, suggesting an absence of compensatory export by other hepatocellular transporters. In conclusion, these data demonstrate that although WT and TR(-) hepatocytes are similar in their conjugative and oxidative metabolism of 4HNE, export of 4HNE-SG is mediated by the MRP2 transporter, a transport system distinct from that involved in HNA efflux.

PMID:
12623073
[PubMed - indexed for MEDLINE]

LinkOut - more resources

Full Text Sources

Other Literature Sources

PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science
    Loading ...
    Support Center