function-altering snps in the human multidrug transporter gene abcb1 identified using a saccharomyces-based assay种代号为abcb1的function-altering snp在人类耐多药转运体基因使用saccharomyces-based试验确定.pdfVIP

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function-altering snps in the human multidrug transporter gene abcb1 identified using a saccharomyces-based assay种代号为abcb1的function-altering snp在人类耐多药转运体基因使用saccharomyces-based试验确定.pdf

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function-altering snps in the human multidrug transporter gene abcb1 identified using a saccharomyces-based assay种代号为abcb1的function-altering snp在人类耐多药转运体基因使用saccharomyces-based试验确定

Function-Altering SNPs in the Human Multidrug Transporter Gene ABCB1 Identified Using a Saccharomyces-Based Assay Hotcherl Jeong1,2, Ira Herskowitz2,3, Deanna L. Kroetz3,4, Jasper Rine1* 1 Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California, United States of America, 2 Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California, United States of America, 3 Institute for Human Genetics, University of California San Francisco, San Francisco, California, United States of America, 4 Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, California, United States of America The human ABCB1 (MDR1)-encoded multidrug transporter P-glycoprotein (P-gp) plays a major role in disposition and efficacy of a broad range of drugs including anticancer agents. ABCB1 polymorphisms could therefore determine interindividual variability in resistance to these drugs. To test this hypothesis we developed a Saccharomyces-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) or decreased (W1108R) drug resistance. The R669C allele’s highly elevated resistance was compromised when 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 robust new methodology for identification of function-altering polymorphisms in human multidrug transporter genes,