Function-altering SNPs in the human multidrug transporter gene ABCB1 identified using a Saccharomyces-based assay

PLoS Genet. 2007 Mar 9;3(3):e39. doi: 10.1371/journal.pgen.0030039.


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, identified polymorphisms affecting P-gp function, and provided a step toward genotype-determined dosing of chemotherapeutics.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents / pharmacology
  • Conserved Sequence
  • Daunorubicin / pharmacology
  • Doxorubicin / pharmacology
  • Drug Resistance, Fungal / drug effects
  • Evolution, Molecular
  • Genetic Complementation Test
  • Haplotypes
  • Humans
  • Mutant Proteins / metabolism
  • Organic Anion Transporters / chemistry
  • Organic Anion Transporters / genetics*
  • Organic Anion Transporters / metabolism*
  • Polymorphism, Single Nucleotide / genetics*
  • Protein Structure, Secondary
  • Protein Transport / drug effects
  • Saccharomyces cerevisiae / cytology
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism*
  • Subcellular Fractions / drug effects
  • Subcellular Fractions / metabolism
  • Substrate Specificity / drug effects


  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents
  • Mutant Proteins
  • Organic Anion Transporters
  • Doxorubicin
  • Daunorubicin

Associated data

  • OMIM/144700
  • OMIM/168600
  • OMIM/266600