Expression of members of the multidrug resistance protein family in human term placenta

St‐Pierre, Marie V.; Serrano, María A.; Macı́as, Rocı́o I.R.; Dubs, U.; Hoechli, Mathias; Lauper, Urs; Meier, Peter J.; Marin, J. J. G.

doi:10.1152/ajpregu.2000.279.4.r1495

Cited by 280 publications

(225 citation statements)

References 41 publications

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“…The higher transfer rates of methadone in the fetal to maternal direction could be explained by the activity of the unidirectional transporter P-gp. The explanation, though speculative, was based on the localization of P-gp on the brush-border membranes of human trophoblast cells and its activity as an ATP-dependent unidirectional efflux transporter [9,32]. Indeed, the activity of P-gp in the unidirectional efflux of digoxin, vinblastine, and vincristine has been reported in Be-Wo human placental choriocarcinoma epithelial cells [11].…”

Section: Discussionmentioning

confidence: 99%

Role of P-glycoprotein in transplacental transfer of methadone

Nanovskaya

Nekhayeva

Karunaratne

et al. 2005

Biochemical Pharmacology

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Methadone is the therapeutic agent of choice for treatment of the pregnant opiate addict. However, little is known on the factors affecting its concentration in the fetal circulation during pregnancy and how it might relate to neonatal outcome. Therefore, a better understanding of the function of placental metabolic enzymes and transporters should add to the knowledge of the role of the tissue in the disposition of methadone and its relation to neonatal outcome. We hypothesized that the expression and activity of the placental efflux transporter P-glycoprotein (P-gp) would affect the transfer of methadone to the fetal circulation. Data obtained utilizing dual perfusion of placental lobule and monolayers of Be-Wo cell line indicated that methadone is extruded by P-gp. Transfer of methadone to the fetal circuit was increased by 30% in the presence of the P-gp inhibitor GF120918 while the transfer of paclitaxel, a typical substrate of the glycoprotein, was increased by 50%. In the Be-Wo cell line, methadone and paclitaxel uptake was also increased in the presence of the P-gp inhibitor cyclosporin A. Moreover, the expression of P-gp in placental brush-border membranes varied between term placentas. Taken together, these data strongly suggest that the concentration of methadone in the fetal circulation is affected by the expression and activity of P-gp. It is reasonable to speculate that placental disposition of methadone affects its concentration in the fetal circulation. If true, this may also be directly related to the incidence and intensity of neonatal abstinence syndrome (NAS).

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Section: Discussionmentioning

confidence: 99%

Role of P-glycoprotein in transplacental transfer of methadone

Nanovskaya

Nekhayeva

Karunaratne

et al. 2005

Biochemical Pharmacology

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“…The subsequent identification of Abcc2 in the apical membrane of proximal tubule epithelial cells of rat kidney was the first demonstration of an extrahepatic localization of this conjugate efflux pump [150]. Besides human kidney [151], other polarized human tissues with ABCC2 being present in the apical membrane of the polarized cells include the small intestine [38,147], colon [91], gallbladder [144], bronchi [91,147], and placenta [159] (Fig. 1).…”

Section: Localization Of Abcc2 In Polarized Cells and Tissuesmentioning

confidence: 99%

The apical conjugate efflux pump ABCC2 (MRP2)

Nies

Keppler

2006

Pflugers Arch - Eur J Physiol

358

255

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ABCC2 is a member of the multidrug resistance protein subfamily localized exclusively to the apical membrane domain of polarized cells, such as hepatocytes, renal proximal tubule epithelia, and intestinal epithelia. This localization supports the function of ABCC2 in the terminal excretion and detoxification of endogenous and xenobiotic organic anions, particularly in the unidirectional efflux of substances conjugated with glutathione, glucuronate, or sulfate, as exemplified by leukotriene C 4 , bilirubin glucuronosides, and some steroid sulfates. The hepatic ABCC2 pump contributes to the driving forces of bile flow. Acquired or hereditary deficiency of ABCC2, the latter known as Dubin-Johnson syndrome in humans, causes an increased concentration of bilirubin glucuronosides in blood because of their efflux from hepatocytes via the basolateral ABCC3, which compensates for the deficiency in ABCC2-mediated apical efflux. In this article we provide an overview on the molecular characteristics of ABCC2 and its expression in various tissues and species. We discuss the transcriptional and posttranscriptional regulation of ABCC2 and review approaches to the functional analysis providing information on its substrate specificity. A comprehensive list of sequence variants in the human ABCC2 gene summarizes predicted and proven functional consequences, including variants leading to Dubin-Johnson syndrome. Keywords

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“…Some members of the MRP family with the ability to transport biliary compounds -MRP1, MPR2, MRP3 and MRP4 -have been identified in human placenta [64,71] . The mRNA expression levels of MRP1 are higher in placenta than in liver; the abundance of MRP2 in the placenta is low compared to liver, and the expression levels of MRP3 and MRP4 are similar and low in both tissues, respectively [64] .…”

Section: Excretion Of Bile Acidsmentioning

confidence: 99%

Excretion of biliary compounds during intrauterine life

Macı́as¹,

Marin²,

Serrano³

2009

WJG

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In adults, the hepatobiliary system, together with the kidney, constitute the main routes for the elimination of several endogenous and xenobiotic compounds into bile and urine, respectively. However, during intrauterine life the biliary route of excretion for cholephilic compounds, such as bile acids and biliary pigments, is very poor. Although very early in pregnancy the fetal liver produces bile acids, bilirubin and biliverdin, these compounds cannot be efficiently eliminated by the fetal hepatobiliary system, owing to the immaturity of the excretory machinery in the fetal liver. Therefore, the potentially harmful accumulation of cholephilic compounds in the fetus is prevented by their elimination across the placenta. Owing to the presence of detoxifying enzymes and specific transport systems at different locations of the placental barrier, such as the endothelial cells of chorionic vessels and trophoblast cells, this organ plays an important role in the hepatobiliary-like function during intrauterine life. The relevance of this excretory function in normal fetal physiology is evident in situations where high concentrations of biliary compounds are accumulated in the mother. This may result in oxidative stress and apoptosis, mainly in the placenta and fetal liver, which might affect normal fetal development and challenge the fate of the pregnancy. The present article reviews current knowledge of the mechanisms underlying the hepatobiliary function of the fetal-placental unit and the repercussions of several pathological conditions on this tandem.

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Expression of members of the multidrug resistance protein family in human term placenta

Cited by 280 publications

References 41 publications

Role of P-glycoprotein in transplacental transfer of methadone

Role of P-glycoprotein in transplacental transfer of methadone

The apical conjugate efflux pump ABCC2 (MRP2)

Excretion of biliary compounds during intrauterine life

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