MDR1 (ABCB1) G1199A (Ser400Asn) polymorphism alters transepithelial permeability and sensitivity to anticancer agents
- Erica L. WoodahlAffiliated withDepartment of Pharmaceutics, University of WashingtonDepartment of Biomedical and Pharmaceutical Sciences, University of Montana
- , Matthew H. CrouthamelAffiliated withDepartment of Pharmaceutics, University of Washington
- , Tot BuiAffiliated withDepartment of Pharmaceutics, University of Washington
- , Danny D. ShenAffiliated withDepartment of Pharmaceutics, University of Washington
- , Rodney J. Y. HoAffiliated withDepartment of Pharmaceutics, University of Washington Email author
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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.
Using stable recombinant epithelial cells expressing wild-type (MDR1 wt ) or G1199A (MDR1 1199A ), anticancer drug sensitivity and transepithelial permeability were evaluated.
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).
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.
KeywordsMDR1 ABCB1 P-Glycoprotein Pharmacogenomics Cancer chemotherapy Transepithelial permeability
- MDR1 (ABCB1) G1199A (Ser400Asn) polymorphism alters transepithelial permeability and sensitivity to anticancer agents
Cancer Chemotherapy and Pharmacology
Volume 64, Issue 1 , pp 183-188
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- Cancer chemotherapy
- Transepithelial permeability
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- Author Affiliations
- 1. Department of Pharmaceutics, University of Washington, Box 357610, Seattle, WA, 98195, USA
- 2. Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT, USA