PT - JOURNAL ARTICLE AU - Ziping Yang AU - Daniel Wu AU - Tot Bui AU - Rodney J. Y. Ho TI - A Novel Human Multidrug Resistance Gene <em>MDR1</em> Variant <em>G571A</em> (G191R) Modulates Cancer Drug Resistance and Efflux Transport AID - 10.1124/jpet.108.138313 DP - 2008 Nov 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 474--481 VI - 327 IP - 2 4099 - http://jpet.aspetjournals.org/content/327/2/474.short 4100 - http://jpet.aspetjournals.org/content/327/2/474.full SO - J Pharmacol Exp Ther2008 Nov 01; 327 AB - 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 MDR1571A 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 MDR1571A, compared with MDR1wt, paralleled the intracellular drug levels. These data suggest that individuals with this novel MDR1 variant, the 571A genotype, may be more sensitive to the specific anticancer drugs that are Pgp substrates. The American Society for Pharmacology and Experimental Therapeutics