Function-Altering SNPs in the Human Multidrug Transporter Gene ABCB1 Identified Using a Saccharomyces-Based Assay 英文参考文献.docVIP

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Function-Altering SNPs in the Human Multidrug Transporter Gene ABCB1 Identified Using a Saccharomyces-Based Assay 英文参考文献.doc

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Function-Altering SNPs in the Human Multidrug Transporter Gene ABCB1 Identified Using a Saccharomyces-Based Assay 英文参考文献

Function-AlteringSNPsintheHuman MultidrugTransporterGeneABCB1Identified UsingaSaccharomyces-BasedAssay Hotcherl Jeong1,2,Ira Herskowitz2,3,Deanna L.Kroetz3,4,Jasper Rine1* 1DepartmentofMolecularandCellBiology,UniversityofCaliforniaBerkeley,Berkeley,California,UnitedStatesofAmerica,2DepartmentofBiochemistryandBiophysics, UniversityofCaliforniaSanFrancisco,SanFrancisco,California,UnitedStatesofAmerica,3InstituteforHumanGenetics,UniversityofCaliforniaSanFrancisco,SanFrancisco, California,UnitedStatesofAmerica,4DepartmentofBiopharmaceuticalSciences,UniversityofCaliforniaSanFrancisco,SanFrancisco,California,UnitedStatesofAmerica ThehumanABCB1(MDR1)-encodedmultidrugtransporterP-glycoprotein(P-gp)playsamajorroleindispositionand efficacy of a broad range of drugs including anticancer agents. ABCB1 polymorphisms could therefore determine interindividualvariabilityinresistancetothesedrugs.TotestthishypothesiswedevelopedaSaccharomyces-based assay for evaluating the functional significance of ABCB1 polymorphisms. The P-gp reference and nine variants carrying amino-acid–altering single nucleotide polymorphisms (SNPs) were tested on medium containing daunorubicin, doxorubicin, valinomycin, or actinomycin D, revealing SNPs that increased (M89T, L662R, R669C, and S1141T)ordecreased(W1108R)drugresistance.TheR669Callele’shighlyelevatedresistancewascompromisedwhen in combination with W1108R. Protein level or subcellular location of each variant did not account for the observed phenotypes. The relative resistance profile of the variants differed with drug substrates. This study established a robustnewmethodologyforidentificationoffunction-alteringpolymorphismsinhumanmultidrugtransportergenes, identified polymorphisms affecting P-gp function, and provided a step toward genotype-determined dosing of chemotherapeutics. Citation:JeongH,HerskowitzI,KroetzDL,RineJ(2007)Function-alteringSNPsinthehumanmultidrugtransportergene ABCB1identifiedusingaSaccharomyces-based assay.PLoS