Abstract
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.
Highlights
P-glycoprotein (P-gp), a transporter relation to multidrug resistance, is encoded by the human multidrug resistance gene (ABCB1, MDR1)
Progesterone at 0.4 μM up-regulated levels of both types of mRNA three-fold, while estradiol caused only slight increases in the level of either mRNA. These results suggest that estrogens and progestins can regulate ABCB1 transcription, and that this regulation is significantly affected by the 1199G > A polymorphism in the case of some hormones but not others
Polymorphism on hormones up-regulation P-gp mRNA, protein and ATPase activity in vivo were not reported and need further investigations. These findings show that modulation of P-gp activity by steroid sex hormones may give rise to different pharmacokinetics and outcomes of chemotherapy in patients, depending on their genotype at the ABCB1 1199G > A polymorphism
Summary
P-glycoprotein (P-gp), a transporter relation to multidrug resistance, is encoded by the human multidrug resistance gene (ABCB1, MDR1). P-gp expression and activity vary substantially in the population, leading to significant differences in the pharmacokinetics and efficacy of chemotherapeutics. This variability in P-gp likely reflects, at least in part, genetic variability in the ABCB1 gene. More than 60 single-nucleotide polymorphisms (SNPs) have been identified in ABCB1, including several in the protein-coding region (rs1128503, 1236C > T; rs2032582, 2677G > T/A; rs1045642, 3435C > T) [3,4]. Understanding the influence of the reported SNPs on P-gp expression and activity may help in overcoming multidrug resistance and in compensating for inter-patient differences in chemotherapeutic efficacy through personalized medicine
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