Vinblastine and sulfinpyrazone export by the multidrug resistance protein MRP2 is associated with glutathione export.
Article Details
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Evers R, de Haas M, Sparidans R, Beijnen J, Wielinga PR, Lankelma J, Borst P
Vinblastine and sulfinpyrazone export by the multidrug resistance protein MRP2 is associated with glutathione export.
Br J Cancer. 2000 Aug;83(3):375-83.
- PubMed ID
- 10917554 [ View in PubMed]
- Abstract
The multidrug resistance proteins MRP1 and MRP2 are members of the same subfamily of ATP-binding cassette transporters. Besides organic molecules conjugated to negatively charged ligands, these proteins also transport cytotoxic drugs for which no negatively charged conjugates are known to exist. In polarized MDCKII cells, MRP1 routes to the lateral plasma membrane, and MRP2 to the apical plasma membrane. In these cells MRP1 transports daunorubicin, and MRP2 vinblastine; both transporters export reduced glutathione (GSH) into the medium. We demonstrate that glutathione transport in MDCKII-MRP1 cells is inhibited by the inhibitors of organic anion transporters sulfinpyrazone, indomethacin, probenecid and benzbromarone. In MDCKII-MRP2 cells, GSH export is stimulated by low concentrations of sulfinpyrazone or indomethacin, whereas export is inhibited down to control levels at high concentrations. We find that unmodified sulfinpyrazone is a substrate for MRP2, also at concentrations where GSH export is inhibited. We also show that GSH export in MDCKII-MRP2 cells increases in the presence of vinblastine, and that the stoichiometry between drug and GSH exported is between two and three. Our data indicate that transport of sulfinpyrazone and vinblastine is associated with GSH export. However, at high sulfinpyrazone concentrations this compound is transported without GSH. Models of MRP action are discussed that could explain these results.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Sulfinpyrazone Canalicular multispecific organic anion transporter 1 Protein Humans YesInhibitorDetails Sulfinpyrazone Multidrug resistance-associated protein 1 Protein Humans YesInhibitorDetails - Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Daunorubicin Multidrug resistance-associated protein 1 Protein Humans UnknownSubstrateInhibitorDetails Glutathione Multidrug resistance-associated protein 1 Protein Humans UnknownSubstrateInhibitorDetails Indomethacin Multidrug resistance-associated protein 1 Protein Humans UnknownInhibitorDetails Probenecid Multidrug resistance-associated protein 1 Protein Humans UnknownInhibitorDetails Sulfinpyrazone Canalicular multispecific organic anion transporter 1 Protein Humans UnknownSubstrateInhibitorDetails Sulfinpyrazone Multidrug resistance-associated protein 1 Protein Humans UnknownInhibitorDetails