A novel MDR1 G1199T variant alters drug resistance and efflux transport activity of P-glycoprotein in recombinant Hek cells
- PMID: 16917872
- DOI: 10.1002/jps.20743
A novel MDR1 G1199T variant alters drug resistance and efflux transport activity of P-glycoprotein in recombinant Hek cells
Abstract
The human multidrug resistance gene MDR1 encodes the protein product P-glycoprotein (P-gp). P-gp is an integral membrane protein which mediates ATP-dependent substrate efflux. We recently discovered a novel G --> T variant at 1199 nucleotide position of MDR1 which exhibits a 2.3% allelic frequency in leukemia patients. The functional effects of this MDR1-G1199T variant were evaluated with recombinant HEK cells that stably express the wild-type, G1199A, or G1199T variant of the MDR1 protein, P-gp, at comparable levels. A panel of cytotoxic P-gp substrates comprising doxorubicin, vinblastine, vincristine, paclitaxel, or topotecan (a poor P-gp substrate) was used to evaluate the functional impact of G1199 variations. Compared to MDR1(wt), MDR1(G1199A) exhibited an increased resistance to doxorubicin, paclitaxel, vinblastine, and vincristine. In contrast, MDR1(G1199T) reduced resistance to (1/4) that of MDR1(wt) for all drugs except topotecan. Expression of MDR1 exhibits some degree of resistance to topotecan, but 1199 variation has no impact. These data were consistent with the variation in intracellular doxorubicin concentrations measured in MDR1 recombinant cells. Our results suggest that patients with the novel MDR1-G1199T variant may exhibit a lower degree of MDR1 dependent chemoresistance, and those with the G1199A polymorphism may exhibit a higher degree of resistance, compared with MDR1 wild-type patients.
(c) 2006 Wiley-Liss, Inc. and the American Pharmacists Association
Similar articles
-
A novel human multidrug resistance gene MDR1 variant G571A (G191R) modulates cancer drug resistance and efflux transport.J Pharmacol Exp Ther. 2008 Nov;327(2):474-81. doi: 10.1124/jpet.108.138313. Epub 2008 Aug 22. J Pharmacol Exp Ther. 2008. PMID: 18723777 Free PMC article.
-
MDR1 C2005T polymorphism changes substrate specificity.Cancer Chemother Pharmacol. 2010 Aug;66(3):617-23. doi: 10.1007/s00280-010-1308-y. Epub 2010 Mar 23. Cancer Chemother Pharmacol. 2010. PMID: 20309692
-
MDR1 haplotypes significantly minimize intracellular uptake and transcellular P-gp substrate transport in recombinant LLC-PK1 cells.J Pharm Sci. 2006 Oct;95(10):2293-308. doi: 10.1002/jps.20717. J Pharm Sci. 2006. PMID: 16883550
-
Multidrug resistance in cells transfected with human genes encoding a variant P-glycoprotein and glutathione S-transferase-pi.Mol Pharmacol. 1990 Jun;37(6):801-9. Mol Pharmacol. 1990. PMID: 1972772
-
A novel MDR1 GT1292-3TG (Cys431Leu) genetic variation and its effect on P-glycoprotein biologic functions.AAPS J. 2010 Dec;12(4):548-55. doi: 10.1208/s12248-010-9216-y. Epub 2010 Jul 10. AAPS J. 2010. PMID: 20623213 Free PMC article.
Cited by
-
Effects of Garlic on Cytochromes P450 2C9- and 3A4-Mediated Drug Metabolism in Human Hepatocytes.Sci Pharm. 2010 Jul-Sep;78(3):473-81. doi: 10.3797/scipharm.1002-11. Epub 2010 Jun 9. Sci Pharm. 2010. PMID: 20936048 Free PMC article.
-
Do pharmacokinetic polymorphisms explain treatment failure in high-risk patients with neuroblastoma?Eur J Clin Pharmacol. 2011 May;67 Suppl 1(Suppl 1):87-107. doi: 10.1007/s00228-010-0966-3. Epub 2011 Feb 2. Eur J Clin Pharmacol. 2011. PMID: 21287160 Free PMC article. Review.
-
Substrate-dependent effects of human ABCB1 coding polymorphisms.J Pharmacol Exp Ther. 2008 May;325(2):435-42. doi: 10.1124/jpet.107.135194. Epub 2008 Feb 20. J Pharmacol Exp Ther. 2008. PMID: 18287207 Free PMC article.
-
Effect of ABCB1 most frequent polymorphisms on the accumulation of bictegravir in recombinant HEK293 cell lines.Sci Rep. 2024 Jul 15;14(1):16290. doi: 10.1038/s41598-024-66809-0. Sci Rep. 2024. PMID: 39009738 Free PMC article.
-
Mapping the Role of P-gp in Multidrug Resistance: Insights from Recent Structural Studies.Int J Mol Sci. 2025 Apr 28;26(9):4179. doi: 10.3390/ijms26094179. Int J Mol Sci. 2025. PMID: 40362415 Free PMC article. Review.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Medical
Miscellaneous