Molecular Mechanism of the Effects of ABCB1 (1199 G/A) Gene polymorphisms on Transportation of Imatinib Mesylate
- VernacularTitle:ABCB1（1199 G/A）基因多态性对甲磺酸伊马替尼转运的分子机制
- Author:
Ruidan BAI
;
Hong ZHANG
;
Rui PENG
;
Cuiyuan HUANG
- Keywords:
P-gp;
ABCB1;
Single nucleotide polymorphism;
Transmembrane permeability;
Individual medication
- From:
China Pharmacist
2017;20(1):20-24
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To explore the effect of P-glycoprotein ( P-gp) activity on its mediated imatinib mesylate accumulation and intracellular drug membrane permeability. Methods: 1199G/wt ABCB1 and 1199A/mut recombinant plasmids were transferred into HEK293 cells, respectively, and the expression levels of mRNA in different cell models were investigated by RT-PCR. Cell Counting Kit-8(CCK-8) assay was used to detect the drug toxicity in different cell models, HPLC was applied to determine the drug concentra-tion in different cell models and evaluate the intracellular accumulation, and transmembrane resistance experiment was employed to de-tect the transmembrane permeability and evaluate the effect of P-gp activity on drug transportation. Results: Cytotoxicity test showed that the drug concentration in the transferred cells was lower than that in the control group, which proved that P-gp had the function of mediating drug out of cells. HPLC and transepithelial electrical resistance experiment showed that compared with the wild type of AB-CB1 (1199G) cells, mutation of ABCB1 1199A cells had stronger effect on P-gp mediated mesylate imatinib accumulation and drug membrane permeability. Conclusion:The experiment manifested that ABCB1 (1199G/A) site mutation can change the coding protein P-gp activity and the polymorphisms will lead to the increase of mesylate imatinib clearance rate and the decrease of effective drug con-centration in target cells. Meanwhile, the clarification of ABCB1 genetic types in clinics can guide the individualized medication of imatinib mesylate.
