A novel human multidrug resistance gene MDR1 variant G571A (G191R) modulates cancer drug resistance and efflux transport.

The Journal of Pharmacology and Experimental Therapeutics
Ziping YangRodney J Y Ho

Abstract

The human multidrug resistance gene MDR1 encodes a membrane-bound transporter P-glycoprotein (Pgp) that confers the drug resistance of cancer cells by mediating an ATP-dependent drug efflux transport. We and others have reported a number of functionally significant MDR1 variants, including G1199A and G1199T, that modulate cancer drug resistance and intracellular levels of antivirals. In this report, we describe a novel G571A variant of MDR1 detected in 6.4% of leukemia patients. Because this nucleotide modification gives rise to an amino acid change from Gly to Arg at the 191 amino acid position of Pgp, we have developed and characterized the functional affect of the G571A variant in stable, recombinant cells. Using six chemotherapeutic drugs, doxorubicin HCl, daunorubicin HCl, vinblastine sulfate, vincristine sulfate, taxanes (paclitaxel), and epipodophyllotoxin (etoposide, VP-16), we found that the MDR1(571A) variant selectively reduced the degree of Pgp-mediated resistance in drug-dependent manner. Although there was a minimal effect on doxorubicin and daunorubicin, the MDR1-dependent resistance on vinblastine, vincristine, paclitaxel, and etoposide was reduced by approximately 5-fold. The increased drug sensitivity in MDR1(...Continue Reading

References

Oct 1, 1996·Current Opinion in Genetics & Development·M M GottesmanS V Ambudkar
Apr 15, 1997·Proceedings of the National Academy of Sciences of the United States of America·A H SchinkelP Borst
May 20, 1999·Annual Review of Pharmacology and Toxicology·S V AmbudkarM M Gottesman
Aug 23, 2000·Molecular Pharmacology·C MartinR Callaghan
Aug 15, 2001·Clinical Pharmacology and Therapeutics·R B KimG R Wilkinson
Jun 18, 2002·Molecular Pharmacology·Chava Kimchi-SarfatyMichael M Gottesman
Nov 12, 2002·Clinical Pharmacology and Therapeutics·Andreas JohneIvar Roots
Aug 2, 2003·Pharmacogenetics·Deanna L KroetzUNKNOWN Pharmacogenetics of Membrane Transporters Investigators
Jan 7, 2004·Drug Metabolism Reviews·Jiunn H Lin, Masayo Yamazaki
Apr 22, 2004·The Journal of Pharmacology and Experimental Therapeutics·Erica L WoodahlRodney J Y Ho
Jun 24, 2004·Pharmaceutical Research·Christiane Pauli-Magnus, Deanna L Kroetz
Jun 15, 2006·World Journal of Gastroenterology : WJG·V AnneseA Andriulli
Dec 23, 2006·Science·Chava Kimchi-SarfatyMichael M Gottesman

❮ Previous
Next ❯

Citations

Feb 3, 2011·European Journal of Clinical Pharmacology·Francesco BellantiOscar Della Pasqua
May 31, 2011·Pharmacogenomics·Bruno Stieger, Peter J Meier
Aug 28, 2014·Expert Opinion on Drug Metabolism & Toxicology·Oliver Bruhn, Ingolf Cascorbi
Oct 13, 2009·Infection, Genetics and Evolution : Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases·Rebekah L BenishRajeev K Mehlotra
Jun 19, 2012·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Voja PavlovicAndrija Smelcerovic
Dec 6, 2011·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Voja PavlovicAndrija Smelcerovic
May 15, 2012·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Voja PavlovicGordana Stojanovic
Feb 18, 2017·Clinical Pharmacokinetics·Anton IvanyukThierry Buclin
Aug 29, 2012·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Emiliya ChernevaDenitsa Yancheva
Jan 10, 2019·Nature Communications·Atsushi KodanHiroaki Kato

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antimicrobial Resistance (ASM)

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.

Antimicrobial Resistance

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.

Antivirals

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.

Antivirals (ASM)

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.