Cloning and expression of murine sister of P-glycoprotein reveals a more discriminating transporter than MDR1/P-glycoprotein.
Article Details
- CitationCopy to clipboard
Lecureur V, Sun D, Hargrove P, Schuetz EG, Kim RB, Lan LB, Schuetz JD
Cloning and expression of murine sister of P-glycoprotein reveals a more discriminating transporter than MDR1/P-glycoprotein.
Mol Pharmacol. 2000 Jan;57(1):24-35.
- PubMed ID
- 10617675 [ View in PubMed]
- Abstract
Sister of P-glycoprotein (SPGP), a novel murine cDNA and member of the ATP-binding cassette superfamily highly homologous to P-glycoprotein (Pgp), was cloned. Moreover, its genomic clone was isolated and localized to chromosome 2 by fluorescence in situ hybridization. SPGP was functionally evaluated relative to MDR1 after subcloning SPGP cDNA into a retroviral bicistronic vector capable of expressing both SPGP and the green fluorescent protein. LLC-PK1 and MDCKII cells were transduced with this retrovirus and SPGP-positive clones were isolated. Drug uptake and efflux was compared in cells ectopically expressing either SPGP or human MDR1. SPGP cells had decreased uptake of taurocholate and vinblastine compared with LLC-PK1 cells. Additional studies revealed that vinblastine efflux was accelerated by SPGP compared with LLC-PK1. Further comparison revealed that although MDR1 easily impaired uptake of vincristine, daunomycin, paclitaxel, and digoxin, SPGP had no effect on uptake of these drugs. However, further studies demonstrated that, like MDR1, SPGP effluxed calcein-acetoxymethyl ester (AM). Unlike MDR1, SPGP was incapable of effluxing rhodamine 123. Although cyclosporine A and reserpine blocked calcein-AM transport by MDR1, these drugs had either minimal or no effect, respectively, on blocking SPGP efflux of calcein-AM. In contrast, ditekiren, a linear hexapeptide, readily and preferentially inhibited SPGP efflux of calcein-AM. Further studies with three structural analogs of ditekiren revealed that one analog inhibited SPGP efflux of calcein-AM, although not as potently as ditekiren. These are the first studies to reveal that SPGP has distinct transport properties compared with MDR1.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Daunorubicin P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorInducerDetails Paclitaxel Bile salt export pump Protein Humans NoSubstrateInhibitorDetails Paclitaxel P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorDetails Reserpine Bile salt export pump Protein Humans UnknownInhibitorDetails Taurocholic acid Bile salt export pump Protein Humans UnknownSubstrateInducerDetails Taurocholic acid P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorDetails Vinblastine Bile salt export pump Protein Humans NoSubstrateInhibitorDetails Vinblastine P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorInducerDetails Vincristine Bile salt export pump Protein Humans UnknownSubstrateDetails Vincristine P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorInducerDetails