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Multidrug resistance protein-mediated transport of chlorambucil and melphalan conjugated to glutathione
- Source :
- British Journal of Cancer
- Publication Year :
- 1998
- Publisher :
- Nature Publishing Group, 1998.
-
Abstract
- The human multidrug resistance protein (MRP1) confers resistance of cells to a number of different cytostatic drugs and functions as an export pump for glutathione S-conjugates, glucuronides and other amphiphilic anions. The present study details for the first time MRP1-mediated ATP-dependent transport of various glutathione S-conjugates of the bifunctional alkylating agents chlorambucil and melphalan. In membrane vesicles prepared from cells expressing recombinant MRP1, the conjugates were transported at rates in the following order: monoglutathionyl chlorambucil > bisglutathionyl chlorambucil > monohydroxy monoglutathionyl chlorambucil and monoglutathionyl melphalan > monohydroxy monoglutathionyl melphalan. In addition, we show that membranes from chlorambucil-resistant GST-alpha-overexpressing CHO cells as well as from their parental cells express the hamster homologue of MRP1. With both CHO cell membrane preparations, we observed ATP-dependent transport of monoglutathionyl chlorambucil and of leukotriene C4, a glutathione S-conjugate and high-affinity substrate of MRP1. The transport rates measured in the resistant cells were only two- to three-fold higher than those measured in the control cells. These results together with cytotoxicity assays comparing MRP1-overexpressing cell pairs with the CHO cell pair indicate that, although MRP1-mediated transport is active, it may not be the rate-limiting step in chlorambucil resistance in these cell lines. Images Figure 3
- Subjects :
- Melphalan
Cancer Research
Molecular Sequence Data
Drug Resistance
Biological Transport, Active
CHO Cells
Biology
Mass Spectrometry
chemistry.chemical_compound
immune system diseases
hemic and lymphatic diseases
Cricetinae
medicine
Tumor Cells, Cultured
Animals
Humans
Buthionine sulfoximine
Amino Acid Sequence
Antineoplastic Agents, Alkylating
Buthionine Sulfoximine
Chlorambucil
Chinese hamster ovary cell
Cell Membrane
Glutathione
Membrane transport
Leukotriene C4
DNA-Binding Proteins
Oncology
chemistry
Biochemistry
Cell culture
Mediated transport
MutS Homolog 3 Protein
Multidrug Resistance-Associated Proteins
Sequence Alignment
medicine.drug
Research Article
HeLa Cells
Subjects
Details
- Language :
- English
- ISSN :
- 15321827 and 00070920
- Volume :
- 77
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- British Journal of Cancer
- Accession number :
- edsair.doi.dedup.....ae6b85422fd195a9ae7126fa21d057cc