Cannabidiol enhances xenobiotic permeability through the human placental barrier by direct inhibition of breast cancer resistance protein: an ex vivo study

Feinshtein, Valeria; Erez, Offer; Ben‐Zvi, Zvi; Eshkoli, Tamar; Sheizaf, Boaz; Sheiner, Eyal; Holcberg, Gershon

doi:10.1016/j.ajog.2013.08.005

Cited by 60 publications

(46 citation statements)

References 76 publications

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“…BeWo and Jar cells were obtained from Dr. B. Ugele, Ludwig-Maximilians University, Munich, Germany (Feinshtein et al, 2010; Polachek et al, 2010; Feinshtein et al, 2013). MCF7/P-gp cells (BCRP expressing and P-gp induced cells), were kindly provided by Prof. Esther Priel (Ben Gurion University, Beer Sheva, Israel) (Feinshtein et al, 2013).…”

Section: Methodsmentioning

confidence: 99%

“…MCF7/P-gp cells (BCRP expressing and P-gp induced cells), were kindly provided by Prof. Esther Priel (Ben Gurion University, Beer Sheva, Israel) (Feinshtein et al, 2013). All materials for cell culture were purchased from Biological Industries (Israel).…”

Section: Methodsmentioning

confidence: 99%

“…We have already assessed the interaction of CBD with placental BCRP, finding that in both, in vitro and ex vivo systems, CBD inhibited its efflux function (Feinshtein et al, 2013). These results together with other recent findings regarding the effect of cannabinoid on the ABC transporter led us to investigate whether CBD affects placental P-gp on functional and placental P-gp and BCRP on expressional levels (Holland et al, 2006; Zhu et al, 2006; Holland et al, 2007; Holland, Allen & Arnold, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Cannabidiol changes P-gp and BCRP expression in trophoblast cell lines

Feinshtein

Erez

Ben‐Zvi

et al. 2013

PeerJ

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Objectives. Marijuana is the most commonly used illicit drug during pregnancy. Due to high lipophilicity, cannabinoids can easily penetrate physiological barriers like the human placenta and jeopardize the developing fetus. We evaluated the impact of cannabidiol (CBD), a major non-psychoactive cannabinoid, on P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) expression, and P-gp function in a placental model, BeWo and Jar choriocarcinoma cell lines (using P-gp induced MCF7 cells (MCF7/P-gp) for comparison).Study design. Following the establishment of the basal expression of these transporters in the membrane fraction of all three cell lines, P-gp and BCRP protein and mRNA levels were determined following chronic (24–72 h) exposure to CBD, by Western Blot and qPCR. CBD impact on P-gp efflux function was examined by uptake of specific P-gp fluorescent substrates (calcein-AM, DiOC2(3) and rhodamine123(rh123)). Cyclosporine A (CsA) served as a positive control.Results. Chronic exposure to CBD resulted in significant changes in the protein and mRNA levels of both transporters. While P-gp was down-regulated, BCRP levels were up-regulated in the choriocarcinoma cell lines. CBD had a remarkably different influence on P-gp and BCRP expression in MCF7/P-gp cells, demonstrating that these are cell type specific effects. P-gp dependent efflux (of calcein, DiOC2(3) and rh123) was inhibited upon short-term exposure to CBD.Conclusions. Our study shows that CBD might alter P-gp and BCRP expression in the human placenta, and inhibit P-gp efflux function. We conclude that marijuana use during pregnancy may reduce placental protective functions and change its morphological and physiological characteristics.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cannabidiol changes P-gp and BCRP expression in trophoblast cell lines

Feinshtein

Erez

Ben‐Zvi

et al. 2013

PeerJ

Self Cite

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“…Cannabidiol inhibited BCRP hence reducing the efflux of mitoxantrone in a concentration dependent manner in BeWo, JAR, and MCF7/P-gp cells. Short-term exposure of cannabidiol also led to an increased fetal to maternal ratio of glyburide (another BCRP substrate) in the ex vivo placental perfusion model (232). …”

Section: Abc Transporters In the Placentamentioning

confidence: 99%

Placental ABC Transporters: Biological Impact and Pharmaceutical Significance

et al. 2016

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The human placenta fulfills a variety of essential functions during prenatal life. Several ABC transporters are expressed in the human placenta, where they play a role in the transport of endogenous compounds and may protect the fetus from exogenous compounds such as therapeutic agents, drugs of abuse, and other xenobiotics. To date, considerable progress has been made toward understanding ABC transporters in the placenta. Recent studies on the expression and functional activities are discussed. This review discusses the placental expression and functional roles of several members of ABC transporter subfamilies B, C, and G including MDR1/P-glycoprotein, the MRPs, and BCRP, respectively. Since placental ABC transporters modulate fetal exposure to various compounds, an understanding of their functional and regulatory mechanisms will lead to more optimal medication use when necessary in pregnancy.

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“…Multiple transporters in the placenta interact with glyburide (Gedeon et al, 2006(Gedeon et al, , 2008a(Gedeon et al, , 2008bHemauer et al, 2010), significant evidence points to the breast cancer resistance protein (BCRP/ABCG2) as the major transporter responsible for the active extrusion of glyburide from the placenta. This has been demonstrated using BCRP-overexpressing cells, Bcrp knockout mice, pregnant rats, human placentas, and human placental vesicles (Pollex et al, 2008(Pollex et al, , 2010Zhou et al, 2008;Feinshtein et al, 2013).…”

Section: Introductionmentioning

confidence: 93%