Cortisol is transported by the multidrug resistance gene product P-glycoprotein

Kalken, C.K. van; Broxterman, Henk J.; Pinedo, H.M.; Feller, N; Dekker, Henk; Lankelma, J.; Giaccone, Giuseppe

doi:10.1038/bjc.1993.54

Cited by 133 publications

(72 citation statements)

References 20 publications

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“…Since P-gP and MRP act as an efflux pump for steroid hormones, such as cortisol, progesterone and aldosterone (Van Kalken et al, 1993;Mulder et al, 1996) and several studies reported a decrease in TK activity as a result of steroid hormone exposure in chicken embryo retina (Naray et al, 1977;Herzfield and Raper, 1980;Tesoriere et al, 1989), verapamil might inhibit the efflux of these compounds, leading to a transient downregulation of dCK. Clinically relevant concentrations of the steroid drug dexamethasone inhibited the effect of gemcitabine in cultured human glioma cells (Rieger et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Increased sensitivity to gemcitabine of P-glycoprotein and multidrug resistance-associated protein-overexpressing human cancer cell lines

et al. 2003

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Gemcitabine (2 0 ,2 0 -difluorodeoxycytidine) is a deoxycytidine analogue that is activated by deoxycytidine kinase (dCK) to its monophosphate and subsequently to its triphosphate dFdCTP, which is incorporated into both RNA and DNA, leading to DNA damage. Multidrug resistance (MDR) is characterised by an overexpression of the membrane efflux pumps P-glycoprotein (P-gP) or multidrug resistance-associated protein (MRP). Gemcitabine was tested against human melanoma, non-small-cell lung cancer, smallcell lung cancer, epidermoid carcinoma and ovarian cancer cells with an MDR phenotype as a result of selection by drug exposure or by transfection with the mdr1 gene. These cell lines were nine-to 72-fold more sensitive to gemcitabine than their parental cell lines. The doxorubicin-resistant cells 2R120 (MRP1) and 2R160 (P-gP) were nine-and 28-fold more sensitive to gemcitabine than their parental SW1573 cells, respectively (Po0.01), which was completely reverted by 25 mM verapamil. In 2R120 and 2R160 cells, dCK activities were seven-and four-fold higher than in SW1573, respectively, which was associated with an increased dCK mRNA and dCK protein. Inactivation by deoxycytidine deaminase was 2.9-and 2.2-fold decreased in 2R120 and 2R160, respectively. dFdCTP accumulation was similar in SW1573 and its MDR variants after 24 h exposure to 0.1 mM gemcitabine, but dFdCTP was retained longer in 2R120 (Po0.001) and 2R160 (Po0.003) cells. 2R120 and 2R160 cells also incorporated four-and six-fold more [ 3 H]gemcitabine into DNA (Po0.05), respectively. P-glycoprotein and MRP1 overexpression possibly caused a cellular stress resulting in increased gemcitabine metabolism and sensitivity, while reversal of collateral gemcitabine sensitivity by verapamil also suggests a direct relation between the presence of membrane efflux pumps and gemcitabine sensitivity.

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Section: Discussionmentioning

confidence: 99%

Increased sensitivity to gemcitabine of P-glycoprotein and multidrug resistance-associated protein-overexpressing human cancer cell lines

et al. 2003

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“…P-gp is also localized in hormone-producing and hormone-responsive organs such as the adrenal gland, the testes, and the placenta (2). Steroid hormones such as cortisol (4), corticosterone (5), and aldosterone (6) have been shown to be transport substrates for P-gp.…”

mentioning

confidence: 99%

Structure-Activity Relationships for Xenobiotic Transport Substrates and Inhibitory Ligands of P-Glycoprotein

Bain¹,

McLachlan²,

LeBlanc³

1997

Environmental Health Perspectives

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“…High expression of Pgp in the ovaries, testes, adrenal glands, and reproductive organs suggests a function closely associated with steroid hormone transport. Steroids such as estrogen, cortisol, corticosterone and aldosterone have been identified as substrates for MDR1-type and mdr1-type Pgps [11,[25][26][27]. On the other hand, the organs with high expression of MDR1-type Pgp also play an important role in systemic detoxification processes [4][5][6][7][8].…”

Section: Discussionmentioning

confidence: 99%

Upregulation of P-Glycoprotein Activity in Porcine Oocytes and Granulosa Cells During In Vitro Maturation

Yokota

Hirano

Urata

et al. 2011

Journal of Reproduction and Development

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Abstract. Multidrug resistance P-glycoprotein (Pgp), coded by the multidrug resistance type I (MDR1/ABCB1) gene, is an energy-dependent efflux pump and functions in systemic detoxification processes. In the present study, the expression and development of Pgp were evaluated in the porcine oocyte during in vitro maturation to compare with the expression of Pgp in cultured granulosa cells. As revealed by Western blotting using anti-human Pgp antibody, a single band of Pgp with an apparent molecular size of 170 kDa was detected in the germinal vesicle stage oocytes. The surface of GV oocyte was positively labeled by immunostaining. In the second metaphase oocyte after culture in the maturation medium containing porcine follicular fluid and human chorionic gonadotropin, the level of Pgp was increased. The elevation of the oocyte Pgp level was associated with increased activity of rhodamine 6G efflux from the oocyte, and its efflux was suppressed by verapamil, an inhibitor of Pgp. Removal of porcine follicular fluid from the maturation medium resulted in little alteration of the oocyte Pgp level. Expression of Pgp was also elevated in cultured porcine granulosa cells during cell maturation when stimulated with follicle-stimulating hormone or luteinizing hormone for 24-48 h. Collectively, the present results indicate that the transporting activity of P-glycoprotein upregulates in porcine oocytes and granulosa cells during exposure to gonadotropins or prior to ovulation. Key words: MDR1, Oocyte maturation, P-glycoprotein, Rhodamine 6G efflux (J. Reprod. Dev. 57: [322][323][324][325][326] 2011) ultidrug resistance P-glycoprotein (Pgp), coded by the multidrug resistance type I (MDR1/ABCB1) gene in humans, is an energy-dependent efflux pump and belongs to the ATP-binding cassette (ABC) transporter superfamily [1]. In rodents, three genes, mdr1a, mdr1b and mdr2, are known [2], but only mdr1a and mdr1b are functional in cells, conferring multidrug resistance during cancer chemotherapy. Mice lacking mdr1a, mdr1b or both genes are very sensitive to digoxin and rhodamine due to their increased absorption and reduced elimination [3]. Pgp is expressed in a number of normal tissues, in which it functions in systemic detoxification processes [4][5][6][7][8]. A primary role of Pgp is to export hydrophobic compounds, lipids, conjugated organic anions and naturally occurring xenotoxins [9,10]. On the other hand, Pgp is also associated with steroid hormone transport in the steroid-producing organs such as the ovary, testis, and adrenal gland. Steroid hormones including estradiol, cortisol, corticosterone and aldosterone have been identified as substrates for Pgp [11,12].In mammals, oocytes are controlled under paracrine factors produced by granulosa and cumulus cells during oocyte development. After ovulation, however, oocytes may develop the metabolic activity and the transporting activity of low molecular substances including naturally occurring xenotoxins. Trophoblasts express Pgp, which may block absorption of hydrophobic xenot...

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Cortisol is transported by the multidrug resistance gene product P-glycoprotein

Cited by 133 publications

References 20 publications

Increased sensitivity to gemcitabine of P-glycoprotein and multidrug resistance-associated protein-overexpressing human cancer cell lines

Increased sensitivity to gemcitabine of P-glycoprotein and multidrug resistance-associated protein-overexpressing human cancer cell lines

Structure-Activity Relationships for Xenobiotic Transport Substrates and Inhibitory Ligands of P-Glycoprotein

Upregulation of P-Glycoprotein Activity in Porcine Oocytes and Granulosa Cells During In Vitro Maturation

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