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ABCC2 (1249G > A) polymorphism implicates altered transport activity for sorafenib.
Danyun Wei1, Hong Zhang1, Rui Peng1
1a Wuhan University Renmin Hospital , Wuhan , China.
Xenobiotica; the Fate of Foreign Compounds in Biological Systems
|November 19, 2016
Summary
The ABCC2 gene polymorphism 1249G>A increases the activity of multidrug resistance-associated protein 2 (MRP2). This leads to greater efflux of sorafenib, impacting cancer treatment efficacy.
Area of Science:
- Pharmacogenomics
- Molecular Biology
- Cancer Therapeutics
Background:
- Multidrug resistance-associated protein 2 (MRP2), encoded by the ABCC2 gene, is a key efflux transporter.
- Genetic variations, like the ABCC2 1249G>A polymorphism (rs2273697), can alter transporter function.
- Understanding these variations is crucial for optimizing drug efficacy, particularly in cancer treatment.
Purpose of the Study:
- To investigate the functional impact of the ABCC2 1249G>A polymorphism on MRP2-mediated sorafenib efflux.
- To determine if this polymorphism affects cellular sensitivity and drug accumulation.
Main Methods:
- Utilized human embryonic kidney 293 (HEK 293) cell lines stably expressing either the ABCC2-1249G or ABCC2-1249A variants.
- Assessed sorafenib sensitivity (IC50) and intracellular sorafenib accumulation in transfected cells.
- Measured ATPase activity of isolated MRP2 protein variants.
Main Results:
- HEK 293 cells overexpressing ABCC2-1249A exhibited significantly higher IC50 values for sorafenib compared to ABCC2-1249G or control cells.
- Intracellular sorafenib accumulation was markedly lower in ABCC2-1249A cells.
- Isolated ABCC2-1249A protein demonstrated increased ATPase activity compared to ABCC2-1249G protein.
Conclusions:
- The ABCC2 1249G>A polymorphism enhances MRP2 ATPase activity.
- This increased activity results in greater efflux of sorafenib from cells.
- The findings suggest implications for personalized cancer therapy based on ABCC2 genotype.
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