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MDR1 C2005T polymorphism changes substrate specificity

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Abstract

Purpose

The current study is to determine the alterations of efflux transport activity to Rh123 and sensitivity to anticancer agents mediated by a MDR1 C2005T polymorphism.

Methods

Expressions of mRNA and protein of MDR1 were measured by real-time PCR and immunoblotting, respectively, and localization of P-glycoprotein (P-gp) by confocal microscopy. Cell cytotoxicity and efflux transport activity were determined by MTT and Rh123 transepithelial permeability assay, respectively.

Results

MDR1 C2005T polymorphism did not affect the expression level of the MDR1 mRNA and protein and had no effect on the trafficking of P-gp to plasma membrane. A cytotoxicity study showed that MDR1wt and MDR1 2005T cells exhibited similar resistance, as measured by IC50 values, to vinblastine (30.3 ± 2.5 vs. 32.5 ± 1.7 nM) and vincristine (104.1 ± 1.9 vs. 110.3 ± 3.5 nM). However, MDR1 2005T cells were less resistant to paclitaxel (28.2 ± 2.1 vs. 91.8 ± 3.5 nM; P < 0.05) and etoposide (119.7 ± 6.5 vs. 546.8 ± 9.5 nM; P < 0.05). The apparent transepithelial permeability ratios of Rh123 in MDR1 wt and MDR1 2005T cells were 2.12 ± 0.46 and 3.64 ± 0.78 (P < 0.05), respectively.

Conclusions

The MDR1 C2005T polymorphism alters the transepithelial permeability of a fluorescent substrate and sensitivity to select cytotoxic agents, which may influence drug disposition and the therapeutic efficacy of some P-gp substrates.

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Acknowledgments

This work was supported by the National Major Project of Science and Technology of China Grant 2009ZX09304, the National Natural Science Foundation of China Grants 30572230 and 30873089, the Natural Science Foundation of Hunan Province of China Grant 08JJ3058, and the Changsha Municipal Science and Technology Plan of China Grant K0802148-31. We also thank Professor Zhao-qian Liu who provided language help.

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None.

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Authors and Affiliations

  1. Institute of Clinical Pharmacology, Central South University, Changsha, China

    Lijuan Liu, Lan Fan, Xiangdong Peng, Dongli Hu & Honghao Zhou

Authors
  1. Lijuan Liu
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  2. Lan Fan
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  3. Xiangdong Peng
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  4. Dongli Hu
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  5. Honghao Zhou
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Corresponding author

Correspondence to Honghao Zhou.

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Liu, L., Fan, L., Peng, X. et al. MDR1 C2005T polymorphism changes substrate specificity. Cancer Chemother Pharmacol 66, 617–623 (2010). https://doi.org/10.1007/s00280-010-1308-y

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  • DOI: https://doi.org/10.1007/s00280-010-1308-y

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