Antiestrogens and steroid hormones: Substrates of the human P-glycoprotein

doi:10.1016/0006-2952(94)90099-X

Biochemical Pharmacology

Volume 48, Issue 2, 19 July 1994, Pages 287-292

https://doi.org/10.1016/0006-2952(94)90099-X Get rights and content

Abstract

Multidrug-resistant (MDR) tumor cells reduce the toxicity of antineoplastic drugs by an energy-dependent active efflux mechanism mediated by the MDR1 gene product, the P-glycoprotein (Pgp). Pgp expressed in cultured Sf9 insect cells has been shown to exhibit a high capacity ATPase activity in the presence of a variety of drugs known to be transported by the Pgp (Sarkadi et al., J Biol Chem267: 4854–4858, 1992). The strict dependence of the Pgp ATPase activity on the presence of transport substrates indicates that the drug-stimulated ATPase activity is a direct reflection of the drug transport function of the Pgp. In the present study, this system has been utilized to investigate the possibility that antiestrogens and steroid hormones are transported by the Pgp. Antiestrogens such as tamoxifen, metabolites of tamoxifen (4-hydroxytamoxifen and N-desmethyltamoxifen), droloxifen, and toremifene stimulated the Pgp ATPase activity, and the maximum stimulation obtained with these agents equalled the maximal stimulation obtained by the best known MDR chemosensitizer, verapamil. Clomifene, nafoxidine and diethylstilbestrol also stimulated the Pgp ATPase activity, with maximal activations 75, 60 and 45% of the verapamil stimulation, respectively. Different degrees of stimulation of the Pgp ATPase activity were also obtained in the presence of steroid hormones such as progesterone, ;β-estradiol, hydrocortisone, and corticosterone. Among these, progesterone is a potent inducer of the Pgp ATPase activity; at 50 μM, this hormone stimulated the Pgp ATPase activity as effectively as verapamil. These results suggest that the antiestrogens and steroid hormones that are known to reverse the multidrug-resistant phenotype do so by directly interacting with Pgp, thus interfering with its anticancer drug-extruding activity.

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Biochemical Pharmacology

Abstract

References (27)

Rational design and preclinical pharmacology of drugs for reversing multidrug resistance

Biochem Pharmacol

Differential transport properties of two mdr gene products are distinguished by progesterone

J Biol Chem

The interaction site for tamoxifen azidine with the bovine estrogen receptor

J Biol Chem

Steroidal and nonsteroidal antiestrogens in breast cancer cells in culture

J Steroid Biochem

Tamoxifen is a ealmodulin antagonist in the activation of cAMP phosphodiesterase

Biochem Biophys Res Commun

A potent and selective photoaffinity probe for the anti-estrogen binding site of rat liver

J Biol Chem

New evidence that the antiestrogen binding site may be a novel growth-promoting histamine receptor which mediates the antiestrogenic and antiproliferative effects of tamoxifen

Biochem Biophys Res Commun

Expression of the human multidrug resistance cDNA in insect cells generates a high activity drug-stimulated membrane ATPase

J Biol Chem

Fluorescent cellular indicators are extruded by the multidrug resistance protein

J Biol Chem

Protein measurement with the Folin phenol reagent

J Biol Chem

Assay of proteins in the presence of interfering materials

Anal Biochem

Progesterone photoaffinity labels P-glycoprotein in multidrug-resistant human leukemic lymphoblasts

J Biol Chem

Progesterone interacts with P-glycoprotein in multidrug-resistant cells and in the endometrium of gravid uterus

J Biol Chem

Cited by (127)

Utilizing non-coding RNA-mediated regulation of ATP binding cassette (ABC) transporters to overcome multidrug resistance to cancer chemotherapy

Predicting disruptions to drug pharmacokinetics and the risk of adverse drug reactions in non-alcoholic steatohepatitis patients

Dose-dependent effects of Hedyotis diffusa extract on the pharmacokinetics of tamoxifen, 4-hydroxytamoxifen, and N-desmethyltamoxifen

Cationic self-nanoemulsifying formulations of tamoxifen with improved biopharmaceutical attributes and anticancer activity: Systematic development and evaluation

Innate Immunity in the CNS: Redefining the relationship between the CNS and its Environment

Multidrug resistance: Physiological principles and nanomedical solutions