PMID: 9187258Jun 1, 1997Paper

Mutations in the sixth transmembrane domain of P-glycoprotein that alter the pattern of cross-resistance also alter sensitivity to cyclosporin A reversal

Molecular Pharmacology
J F MaP W Melera

Abstract

The expression of a P-glycoprotein (Pgp1) cDNA encoding two amino acid substitutions in the sixth transmembrane domain of the protein (G338A339 to A338P339) confers a unique cross-resistance profile that displays preferential resistance to actinomycin D and diminished resistance to colchicine and daunorubicin. We report here that this multidrug-resistant phenotype is also insensitive to reversal by cyclosporin A (CsA) but not verapamil (VRP). However, the ability of VRP to increase the accumulation of [3H]vincristine is poor in both wild-type and mutant transfectants. In contrast, the accumulation of [3H]vincristine in wild-type versus mutant transfectants in the presence of CsA is dramatically increased. It is the substitution of the alanine residue at position 339 with proline that is primarily responsible for the lowered sensitivity to CsA and for the altered drug accumulation levels. Both substitutions are required to confer the unique cross-resistance profile of the double mutant, although each independently confers a specific profile of its own. These results indicate that alterations in Pgp1 structure can differentially affect the activity of CsA and VRP to mediate drug accumulation in multidrug-resistant cells and suppo...Continue Reading

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Citations

Aug 30, 2016·Nature Chemical Biology·Tanvi Shekhar-GuturjaLeah E Cowen
Oct 21, 2003·International Journal of Cancer. Journal International Du Cancer·Miyu MiwaYoshikazu Sugimoto
Jan 31, 2006·FEBS Letters·Annie Frelet, Markus Klein
Dec 8, 2009·The FEBS Journal·Emily Crowley, Richard Callaghan
May 20, 1999·Annual Review of Pharmacology and Toxicology·S V AmbudkarM M Gottesman
Aug 1, 2008·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·S-F Zhou
Mar 21, 2006·Trends in Pharmacological Sciences·Richard A ShillingHendrik W van Veen
Nov 13, 2010·The Journal of Physical Chemistry. B·Jean-Paul BeckerMartine Prévost

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