Effects of steroids and verapamil on P-glycoprotein ATPase activity: progesterone, desoxycorticosterone, corticosterone and verapamil are mutually non-exclusive modulators.
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Orlowski S, Mir LM, Belehradek J Jr, Garrigos M
Effects of steroids and verapamil on P-glycoprotein ATPase activity: progesterone, desoxycorticosterone, corticosterone and verapamil are mutually non-exclusive modulators.
Biochem J. 1996 Jul 15;317 ( Pt 2):515-22.
- PubMed ID
- 8713080 [ View in PubMed]
- Abstract
P-glycoprotein (P-gp) is a membranous ATPase responsible for the multidrug resistance (MDR) phenotype. Using membrane vesicles prepared from the highly resistant cell line DC-3F/ADX we studied the influence of P-gp ATPase activity of four progesterone derivatives which specifically bind to P-gp and reverse MDR. Progesterone and desoxycorticosterone stimulate P-gp ATPase activity with, respectively, apparent concentrations giving half-maximal activation of 20-25 microM and 40-50 microM, and activation factors of 2.3 (at 100 microM progesterone) and 1.8 (at 170 microM desoxycorticosterone). Hydrocortisone above 100 microM stimulates P-gp ATPase activity while corticosterone has no apparent stimulating effect. Our data are consistent with the location of the binding sites for the progesterone derivatives on the P-gp membranous domain. The effects of these steroids on verapamil-stimulated P-gp ATPase activity support a non-competitive mechanism, i.e. the binding sites for verapamil and steroids are mutually non-exclusive for P-gp ATPase modulation. A similar non-competitive inhibition of progesterone-stimulated P-gp ATPase activity by desoxycorticosterone or by corticosterone leads to the conclusion that these steroids, although sharing related structures, have distinct modulating sites on P-gp. As expected from their mutually non-exclusive interactions on P-gp, progesterone and verapamil when mixed induce a synergistic modulation of P-gp ATPase activity. Since drug transport by P-gp is believed to be coupled to its ATPase activity, a corresponding synergistic effect of these two modulators for the inhibition of P-gp-mediated drug resistance can be expected.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Hydrocortisone P-glycoprotein 1 Protein Humans UnknownSubstrateInducerDetails Hydrocortisone aceponate P-glycoprotein 1 Protein Humans UnknownNot Available Details Hydrocortisone acetate P-glycoprotein 1 Protein Humans UnknownNot Available Details Hydrocortisone butyrate P-glycoprotein 1 Protein Humans UnknownNot Available Details Hydrocortisone cypionate P-glycoprotein 1 Protein Humans UnknownNot Available Details Hydrocortisone phosphate P-glycoprotein 1 Protein Humans UnknownNot Available Details Hydrocortisone probutate P-glycoprotein 1 Protein Humans UnknownNot Available Details Hydrocortisone valerate P-glycoprotein 1 Protein Humans UnknownNot Available Details