Steroid Transport, Accumulation, and Antagonism of P-Glycoprotein in Multidrug-Resistant Cells

Barnes, Kevin M.; Dickstein, Bruce; Cutler, Gordon B.; Fojo, Tito; Bates, Susan E.

doi:10.1021/bi952380k

Cited by 154 publications

(122 citation statements)

References 36 publications

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“…However, we were unable to demonstrate any difference in the ability of progesterone to affect vinblastine binding to P-gp1a and P-gp1b. Previous reports, using a range of less direct assay techniques, also failed consistently to distinguish between the two mouse isoforms in terms of steroid binding or transport properties (Ueda et al, 1992;Barnes et al, 1996). Thus, the present data suggest that differences in the ability to transport progesterone are unlikely to account for the duplication giving rise to P-gp1a and P-gp1b.…”

Section: Discussionsupporting

confidence: 58%

The equilibrium and kinetic drug binding properties of the mouse P-gp1a and P-gp1b P-glycoproteins are similar

1999

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SummaryThe gene encoding the multidrug resistance P-glycoprotein (P-gp) is duplicated in rodent species and the functional basis for this remains unresolved. Despite a high sequence similarity, the mouse P-gp1a and P-gp1b isoforms show distinct patterns of tissue distribution which suggest a specific role of the P-gp1b isoform in steroid transport. In the present study possible biochemical differences between the isoforms were directly investigated at the level of drug interaction. There was no detectable difference in the affinity or binding capacity of the two isoforms towards [ 3 H]vinblastine at equilibrium. Similarly, the rate at which [ 3 H]vinblastine associates with P-gp was indistinguishable between the two isoforms. Some modest differences were observed in the relative abilities of the multidrug-resistant (MDR) reversing agents CP100-356, nicardipine and verapamil to displace equilibrium [ 3 H]vinblastine binding to P-gp1a and P-gp1b. The steroid hormone progesterone displayed a low affinity (K i = 1.2 ± 0.2 µM for P-gp1a and 3.5 ± 0.5 µM for P-gp1b), suggesting an unlikely role as a physiological substrate. Thus the mouse isoforms do not appear to exhibit functional differences at the level of initial substrate interaction with protein.

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Section: Discussionsupporting

confidence: 58%

The equilibrium and kinetic drug binding properties of the mouse P-gp1a and P-gp1b P-glycoproteins are similar

1999

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“…[33][34][35] We analyzed the presence of ABCB1 at the surface of MAIT cells and other For personal use only. on May 10, 2018. by guest www.bloodjournal.org From populations sorted according to their expression of several membrane markers.…”

Section: Mait Cells Express Abcb1 and Persist Through Chemotherapymentioning

confidence: 99%

Human MAIT cells are xenobiotic-resistant, tissue-targeted, CD161hi IL-17–secreting T cells

Dusséaux

Martin

Serriari

et al. 2011

Blood

876

1,376

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Mucosal-associated invariant T (MAIT) cells IntroductionMainstream T cells display a very diverse repertoire of antigen receptors, which enable these cells to respond to a wide variety of antigens presented by polymorphic major histocompatibility complex (MHC) molecules. During development, interactions between the T cells and selecting MHC class II and I molecules on thymic epithelial cells lead to the specific features of CD4 and CD8 T-cell lineage. However, 2 "innate-like" T lymphocytes, the natural killer T (NKT) and mucosal-associated invariant T (MAIT) cells, follow different ontogenic pathways with selection by nonpolymorphic MHC class Ib molecules. 1 Human MAIT cells express the semi-invariant T-cell receptor (TCR; iV␣7.2-J␣33) and are selected by the MHC class Ib molecule, MR1 on hematopoietic cells, which confer peculiar features. 2,3 Indeed, MAIT cells are enriched in the intestinal lamina propria and are numerous in the peripheral blood of healthy subjects. They are present in cord blood in small numbers with a naive phenotype, whereas in adults they represent approximately 10% of mature CD8 or CD4 Ϫ CD8 Ϫ (DN) T cells and display an effector-memory phenotype. We recently showed that MAIT cells specifically react against antigen-presenting cells (APCs), fed with a wide variety of bacteria and yeasts but not viruses, and display protective activity in experimental bacterial infection models. 4,5 In humans, they are defined as CD161 hi IL-18R␣ ϩ V␣7.2 ϩ ␥␦ Ϫ CD3 ϩ lymphocytes. 3,4 Either CD161 or IL-18R␣ expression at the cell surface, together with the V␣7.2 segment, allows for the unequivocal identification of MAIT cells in both peripheral blood and tissues. 3,4 CD161 (KLRB1, NKRP1A) is a C-type lectin family member, part of the NK complex. 6 Ligands for CD161 have been described only recently, and blocking or cross-linking CD161 may modulate T-cell functions. 7-9 CD161 is also expressed by the majority of NK cells and diverse subsets of T lymphocytes that include TCR-␥␦ T cells and most NKT cells. CD161 expression is found on a significant proportion of tissue-infiltrating T cells, such as the intestine and liver. [10][11][12] The frequency of these cells varies in certain pathologic conditions, such as cancer and viral or autoimmune diseases. [12][13][14][15] Recently, it has been demonstrated that a subset of naive cord blood CD4 T cells express CD161 and are precursors of peripheral, mature, Th17 T cells. 16 CD161 expression seems to correlate with interleukin-17 (IL-17) secretion by CD4 T cells. 17 Among TCR-␣␤ T cells, most of the CD161 ϩ T cells belong to the CD4 subset. However, CD8 T cells expressing CD161 can also be found, but their nature has just begun to be explored. CD161 ϩ CD8 T cells can be split into 2 different populations expressing intermediate or high levels of CD161. Two recent reports independently raised new findings on this latter subset. The first shows that CD161 hi CD8 T cells represent self-renewing memory cells, which survive chemotherapy. 18 These cells are absent from...

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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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Steroid Transport, Accumulation, and Antagonism of P-Glycoprotein in Multidrug-Resistant Cells

Cited by 154 publications

References 36 publications

The equilibrium and kinetic drug binding properties of the mouse P-gp1a and P-gp1b P-glycoproteins are similar

The equilibrium and kinetic drug binding properties of the mouse P-gp1a and P-gp1b P-glycoproteins are similar

Human MAIT cells are xenobiotic-resistant, tissue-targeted, CD161hi IL-17–secreting T cells

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

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