Journal article
Characterization of multidrug resistance-associated protein 2 in the hepatocellular disposition of 4-hydroxynonenal
Archives of biochemistry and biophysics, Vol.411(2), pp.243-250
2003
DOI: 10.1016/S0003-9861(03)00002-X
PMID: 12623073
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.
Details
- Title: Subtitle
- Characterization of multidrug resistance-associated protein 2 in the hepatocellular disposition of 4-hydroxynonenal
- Creators
- John F Reichard - Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, CO 80262, USAJonathan A Doorn - Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, CO 80262, USAFranz Simon - Division of Gastroenterology, University of Colorado Health Sciences Center, Denver, CO 80262, USAMelinda S Taylor - Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, CO 80262, USADennis R Petersen - Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, CO 80262, USA
- Resource Type
- Journal article
- Publication Details
- Archives of biochemistry and biophysics, Vol.411(2), pp.243-250
- Publisher
- Elsevier Inc
- DOI
- 10.1016/S0003-9861(03)00002-X
- PMID
- 12623073
- ISSN
- 0003-9861
- eISSN
- 1096-0384
- Language
- English
- Date published
- 2003
- Academic Unit
- Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984070973302771
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