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MDR1 (ABCB1) G1199A (Ser400Asn) polymorphism alters transepithelial permeability and sensitivity to anticancer agents

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Abstract

Purpose

P-glycoprotein (P-gp), encoded by MDR1 (or ABCB1), is important in anticancer drug delivery and resistance. We evaluated alterations in P-gp-mediated transport of anticancer agents due to the MDR1 G1199A polymorphism.

Methods

Using stable recombinant epithelial cells expressing wild-type (MDR1 wt ) or G1199A (MDR1 1199A ), anticancer drug sensitivity and transepithelial permeability were evaluated.

Results

The recombinant cells MDR1 wt and MDR1 1199A displayed comparable doxorubicin resistance. However, MDR1 1199A cells displayed greater resistance to vinblastine, vincristine, paclitaxel, and VP-16 (11-, 2.9-, 1.9-, and 2.9-fold, respectively). Alterations in transepithelial permeability paralleled these changes. Efflux of doxorubicin was similar between MDR1 wt - and MDR1 1199A -expressing cells, while P-gp-mediated transport was greater for vinblastine and vincristine in MDR1 1199A cells (2.9- and 2.0-fold, respectively).

Conclusions

The occurrence and magnitude of the MDR1 G1199A effect is drug specific. Overall, the MDR1 G1199A polymorphism may impact anticancer efficacy through modulation of drug distribution and delivery to target tumor cells.

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Abbreviations

MDR1 or ABCB1 :

Multidrug resistance gene

P-gp:

P-glycoprotein

ABC:

ATP-binding cassette

BBB:

Blood–brain-barrier

SNP:

Single nucleotide polymorphism

MDR1 wt :

Wild-type MDR1

MDR1 1199A :

MDR1 G1199A polymorphism

EC50 :

Effective drug concentration necessary for 50% cell death

TEER:

Transepithelial electrical resistance values

P app :

Apparent permeability

P appA→B :

Apical-to-basolateral apparent permeability

P appB→A :

Basolateral-to-apical apparent permeability

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Acknowledgments

Supported in part by NIH grants GM62883, AI52663, NS39178, ES07033, and HL56548. ELW is a recipient of the NIH Pharmaceutical Sciences Training Grant (GM07750), and the William E. Bradley Fellowship in Pharmaceutics. Sequencing work was supported by the University School of Pharmacy DNA Sequencing and Gene Analysis Center. RJYH is also supported by the Milo Gibaldi Endowment.

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Author notes

  1. Erica L. Woodahl

    Present address: Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT, USA

Authors and Affiliations

  1. Department of Pharmaceutics, University of Washington, Box 357610, Seattle, WA, 98195, USA

    Erica L. Woodahl, Matthew H. Crouthamel, Tot Bui, Danny D. Shen & Rodney J. Y. Ho

Authors
  1. Erica L. Woodahl
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  2. Matthew H. Crouthamel
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  3. Tot Bui
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  4. Danny D. Shen
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  5. Rodney J. Y. Ho
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Corresponding author

Correspondence to Rodney J. Y. Ho.

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Woodahl, E.L., Crouthamel, M.H., Bui, T. et al. MDR1 (ABCB1) G1199A (Ser400Asn) polymorphism alters transepithelial permeability and sensitivity to anticancer agents. Cancer Chemother Pharmacol 64, 183–188 (2009). https://doi.org/10.1007/s00280-008-0906-4

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  • DOI: https://doi.org/10.1007/s00280-008-0906-4

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