P-glycoprotein (P-gp/MDR1)-mediated efflux of sex-steroid hormones and modulation of P-gp expression in vitro.
Article Details
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Kim WY, Benet LZ
P-glycoprotein (P-gp/MDR1)-mediated efflux of sex-steroid hormones and modulation of P-gp expression in vitro.
Pharm Res. 2004 Jul;21(7):1284-93.
- PubMed ID
- 15290871 [ View in PubMed]
- Abstract
PURPOSE: To determine whether female sex-steroid hormones and their metabolites can modulate P-glycoprotein (P-gp) expression and catalytic activity and to investigate P-gp mediated transport of these sex-steroids across MDR1-transfected Madine-Darby canine kidney (MDCK) cells. METHODS: Changes in P-gp protein and MDR1 mRNA expression levels were examined in the presence of various estrogens and progestins after a 72-h induction period in the LS180 human colon carcinoma cell line via Western blotting and semiquantitative Reverse-transcription-polymerase chain reaction (RT-PCR), respectively. Concentration-dependent stimulation of vanadate-sensitive P-gp ATPase activity was measured in membranes of Sf9 insect cells infected with a recombinant baculovirus containing the human MDR1 cDNA used with appropriate control membranes. MDCK and MDR1-transfected MDCK cell lines were then used to measure bidirectional P-gp transport of various steroids in the presence and absence of the P-gp inhibitor, GG918. Samples obtained were quantified using LC/MS. RESULTS: Our findings show that P-gp protein levels are inducible by estrone (4-fold over control), estriol (2-fold), and ethynyl estradiol (3-fold). MDR1 mRNA expression levels were also inducible in a concentration-dependent manner from 25 nM to 10 microM. Bidirectional transport studies indicate that ethynyl estradiol, estrone, and estriol are all substrates for P-gp with respective efflux ratios of 10.3, 6.9, and 2.8. Norethindrone was not found to be a substrate for P-gp. Ethynyl estradiol and progesterone were able to significantly stimulate P-gp ATPase activity in a concentration-dependent manner. CONCLUSIONS: Our studies indicate that several sex-steroid hormones are substrates for P-gp-mediated transport and are also able to induce P-gp expression at both the protein and mRNA level in vitro. Stimulation of P-gp ATPase catalytic activity by steroid hormones was also observed, suggesting physical interactions and identifying a need for further investigations to understand the in vivo effects of endogenous and synthetic steroid hormones on the expression and function of P-gp.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Estradiol P-glycoprotein 1 Protein Humans UnknownSubstrateDownregulatorRegulatorDetails Estradiol acetate P-glycoprotein 1 Protein Humans UnknownSubstrateDetails Estradiol benzoate P-glycoprotein 1 Protein Humans UnknownSubstrateDetails Estradiol cypionate P-glycoprotein 1 Protein Humans UnknownSubstrateDetails Estradiol dienanthate P-glycoprotein 1 Protein Humans UnknownSubstrateDetails Estradiol valerate P-glycoprotein 1 Protein Humans UnknownSubstrateDetails Estriol P-glycoprotein 1 Protein Humans UnknownSubstrateInducerDetails Estriol tripropionate P-glycoprotein 1 Protein Humans UnknownNot Available Details Estrone P-glycoprotein 1 Protein Humans UnknownSubstrateInducerDetails Ethinylestradiol P-glycoprotein 1 Protein Humans UnknownSubstrateDetails Progesterone P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorInducerDetails - Pharmaco-transcriptomics
Drug Drug Groups Gene Gene ID Change Interaction Chromosome Estradiol Approved Investigational Vet Approved ABCB1 5243 upregulated Estradiol results in increased expression of ABCB1 mRNA 7q21.12 Estriol Approved Investigational Vet Approved ABCB1 5243 upregulated Estriol results in increased expression of ABCB1 mRNA 7q21.12 Estrone Approved ABCB1 5243 upregulated Estrone results in increased expression of ABCB1 mRNA 7q21.12 Ethinylestradiol Approved ABCB1 5243 upregulated Ethinyl Estradiol results in increased expression of ABCB1 mRNA 7q21.12 Norethisterone Approved ABCB1 5243 upregulated Norethindrone results in increased expression of ABCB1 mRNA 7q21.12 Levonorgestrel Approved Investigational ABCB1 5243 upregulated Levonorgestrel results in increased expression of ABCB1 mRNA 7q21.12 Progesterone Approved Vet Approved ABCB1 5243 upregulated Progesterone results in increased expression of ABCB1 mRNA 7q21.12 Rifampicin Approved ABCB1 5243 upregulated Rifampin results in increased expression of ABCB1 mRNA 7q21.12