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Effects of the ABCB1 (1199G > A) Polymorphism on Steroid Sex Hormone-Induced P-Glycoprotein Expression, ATPase Activity, and Hormone Efflux
This study examined how the 1199G > A polymorphism in the ABCB1 gene encoding P-glycoprotein (P-gp) affects the protein’s expression, ATPase activity, and ability to pump female steroid sex hormones out of LLC-PK1 cells. The ABCB1 (1199G) or ABCB1 (1199A) allele was transfected into cells, which...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5635765/ https://www.ncbi.nlm.nih.gov/pubmed/29083397 http://dx.doi.org/10.3390/medsci3040124 |
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author | Peng, Rui Zhang, Hong Zhang, Ying Wei, Dan-Yun |
author_facet | Peng, Rui Zhang, Hong Zhang, Ying Wei, Dan-Yun |
author_sort | Peng, Rui |
collection | PubMed |
description | This study examined how the 1199G > A polymorphism in the ABCB1 gene encoding P-glycoprotein (P-gp) affects the protein’s expression, ATPase activity, and ability to pump female steroid sex hormones out of LLC-PK1 cells. The ABCB1 (1199G) or ABCB1 (1199A) allele was transfected into cells, which were incubated for 48 h with various hormone concentrations, then analyzed by Western blotting to examine expression of P-gp protein and by reverse transcription-polymerase chain reaction (RT-PCR) to examine expression of mRNA. Cells were also compared in terms of their transepithelial permeability to steroid sex hormones in the presence and absence of the specific P-gp inhibitor GF120918. P-gp ATPase activity induced by steroid sex hormones was also assayed. Estriol and ethynyl estradiol up-regulated levels of ABCB1 mRNA in a concentration-dependent manner, with ABCB1 (1199A) mRNA showing greater up-regulation than ABCB1 (1199G) mRNA. Estrone, estriol, and ethynyl estradiol were substrates of both types of P-gp in transepithelial permeability assays, and the ABCB1 (1199A) protein showed a significantly higher net efflux ratio for estrone (13.4 vs. 7.4, p < 0.005), estriol (5.6 vs. 3.3, p < 0.05), and ethynyl estradiol (12.7 vs. 5.3, p < 0.005). Induction of P-gp ATPase activity by ethynyl estradiol and progesterone increased with increasing hormone concentration, and the magnitude of stimulation was greater for ABCB1 (1199A) P-gp than for ABCB1 (1199G) P-gp. These results indicate that the ABCB1 (1199G > A) polymorphism influences steroid sex hormone-induced expression and function of P-gp, which may help to explain inter-patient differences in P-gp-mediated chemotherapy resistance in vivo. |
format | Online Article Text |
id | pubmed-5635765 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-56357652017-10-26 Effects of the ABCB1 (1199G > A) Polymorphism on Steroid Sex Hormone-Induced P-Glycoprotein Expression, ATPase Activity, and Hormone Efflux Peng, Rui Zhang, Hong Zhang, Ying Wei, Dan-Yun Med Sci (Basel) Article This study examined how the 1199G > A polymorphism in the ABCB1 gene encoding P-glycoprotein (P-gp) affects the protein’s expression, ATPase activity, and ability to pump female steroid sex hormones out of LLC-PK1 cells. The ABCB1 (1199G) or ABCB1 (1199A) allele was transfected into cells, which were incubated for 48 h with various hormone concentrations, then analyzed by Western blotting to examine expression of P-gp protein and by reverse transcription-polymerase chain reaction (RT-PCR) to examine expression of mRNA. Cells were also compared in terms of their transepithelial permeability to steroid sex hormones in the presence and absence of the specific P-gp inhibitor GF120918. P-gp ATPase activity induced by steroid sex hormones was also assayed. Estriol and ethynyl estradiol up-regulated levels of ABCB1 mRNA in a concentration-dependent manner, with ABCB1 (1199A) mRNA showing greater up-regulation than ABCB1 (1199G) mRNA. Estrone, estriol, and ethynyl estradiol were substrates of both types of P-gp in transepithelial permeability assays, and the ABCB1 (1199A) protein showed a significantly higher net efflux ratio for estrone (13.4 vs. 7.4, p < 0.005), estriol (5.6 vs. 3.3, p < 0.05), and ethynyl estradiol (12.7 vs. 5.3, p < 0.005). Induction of P-gp ATPase activity by ethynyl estradiol and progesterone increased with increasing hormone concentration, and the magnitude of stimulation was greater for ABCB1 (1199A) P-gp than for ABCB1 (1199G) P-gp. These results indicate that the ABCB1 (1199G > A) polymorphism influences steroid sex hormone-induced expression and function of P-gp, which may help to explain inter-patient differences in P-gp-mediated chemotherapy resistance in vivo. MDPI 2015-12-01 /pmc/articles/PMC5635765/ /pubmed/29083397 http://dx.doi.org/10.3390/medsci3040124 Text en © 2015 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Peng, Rui Zhang, Hong Zhang, Ying Wei, Dan-Yun Effects of the ABCB1 (1199G > A) Polymorphism on Steroid Sex Hormone-Induced P-Glycoprotein Expression, ATPase Activity, and Hormone Efflux |
title | Effects of the ABCB1 (1199G > A) Polymorphism on Steroid Sex Hormone-Induced P-Glycoprotein Expression, ATPase Activity, and Hormone Efflux |
title_full | Effects of the ABCB1 (1199G > A) Polymorphism on Steroid Sex Hormone-Induced P-Glycoprotein Expression, ATPase Activity, and Hormone Efflux |
title_fullStr | Effects of the ABCB1 (1199G > A) Polymorphism on Steroid Sex Hormone-Induced P-Glycoprotein Expression, ATPase Activity, and Hormone Efflux |
title_full_unstemmed | Effects of the ABCB1 (1199G > A) Polymorphism on Steroid Sex Hormone-Induced P-Glycoprotein Expression, ATPase Activity, and Hormone Efflux |
title_short | Effects of the ABCB1 (1199G > A) Polymorphism on Steroid Sex Hormone-Induced P-Glycoprotein Expression, ATPase Activity, and Hormone Efflux |
title_sort | effects of the abcb1 (1199g > a) polymorphism on steroid sex hormone-induced p-glycoprotein expression, atpase activity, and hormone efflux |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5635765/ https://www.ncbi.nlm.nih.gov/pubmed/29083397 http://dx.doi.org/10.3390/medsci3040124 |
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