Placental P-glycoprotein deficiency enhances susceptibility to chemically induced birth defects in mice

Lankas, George R.; Wise, L. David; Cartwright, Mark E.; Pippert, Todd R.; Umbenhauer, Diane R.

doi:10.1016/s0890-6238(98)00027-6

Cited by 287 publications

(182 citation statements)

References 22 publications

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“…Although the placenta has been considered to be an inefficient barrier to drug distribution between maternal and fetal circulations [23], Lankas et al [14] recently provided evidence of the importance of placental P-gp in a spontaneous "knockout" mice. Their study suggested that the placenta may play more than a passive role in regulating chemical distribution and consequently, differences in blood levels of chemicals between the mother and fetus to the point of influencing fetal development.…”

Section: Discussionmentioning

confidence: 99%

“…Nakamura et al [13] using immunoblotting experiments also showed the expression of P-gp specifically in the human cyto-and syncytio-trophoblasts. Although P-gp in the analogous transporting trophoblast layer (labyrinth) is speculated to play a signficant role in the protection of the rodent fetus from toxic compounds [14], its function, such as transporting activity and substrate specificity in the human cyto-and syncytio-trophoblasts, remain unknown. Also, currently no information exists regarding the presence of a functional multidrug resistant associated protein (MRP) in the placenta.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Functional expression of P-glycoprotein in primary cultures of human cytotrophoblasts and BeWo cells☆

Utoguchi

Chandorkar

Avery

et al. 2000

Reproductive Toxicology

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Functional expression of P-glycoprotein in primary cultures of human cytotrophoblasts and BeWo cells☆

Utoguchi

Chandorkar

Avery

et al. 2000

Reproductive Toxicology

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“…7 Recent studies in knockout mice have effectively illustrated the relevance of placental transport mechanisms, e.g., P-glycoprotein, in protecting the fetus from exposure to chemicals. 21 Consequently, the recognition of transport mechanisms is important for developing an understanding of the molecular mechanisms and role of the trophoblast in regulating drug passage across the placental barrier. …”

Section: Discussionmentioning

confidence: 99%

Carrier-mediated transport of monocarboxylic acids in BeWo cell monolayers as a model of the human trophoblast

Utoguchi

Magnusson

Audus

1999

Journal of Pharmaceutical Sciences

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“…Similarly, the kidney and liver expel such substances into the urine and bile through Pgp [28]. Pgp is expressed on both the luminal and abluminal membranes of the testicular and ovarian endothelium and serves to expel its substrates from endothelial cells [29] and may in turn participate in the protection of germ cells in the organs. It is noteworthy that the expression and function of Pgp were increased during in vitro oocyte maturation.…”

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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Placental P-glycoprotein deficiency enhances susceptibility to chemically induced birth defects in mice

Cited by 287 publications

References 22 publications

Functional expression of P-glycoprotein in primary cultures of human cytotrophoblasts and BeWo cells☆

Functional expression of P-glycoprotein in primary cultures of human cytotrophoblasts and BeWo cells☆

Carrier-mediated transport of monocarboxylic acids in BeWo cell monolayers as a model of the human trophoblast

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

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