Abstract
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.
Highlights
Until recently it was assumed that prenatal exposure to marijuana is frequently combined with other drugs, making cannabis effects difficult to isolateHow to cite this article Feinshtein et al (2013), Cannabidiol changes P-gp and Breast Cancer Resistance Protein (BCRP) expression in trophoblast cell lines
CBD impact on BCRP and P-gp protein expression The changes in P-gp and BCRP protein levels in the membrane fraction of BeWo, Jar and MCF7/Pgp cells were studied
For BCRP (ABCG2), results were confirmed by FACS analysis, showing that BCRP expression was much higher in JAR cells compared to BeWo cells (Fig. 1D)
Summary
Until recently it was assumed that prenatal exposure to marijuana is frequently combined with other drugs (e.g., tobacco and alcohol), making cannabis effects difficult to isolateHow to cite this article Feinshtein et al (2013), Cannabidiol changes P-gp and BCRP expression in trophoblast cell lines. The presence of the endocannabinoid receptors CB1 and CB2 on placental syncytiotrophoblast (Habayeb et al, 2008a), along with marijuana being the most popular drug of abuse among pregnant population (Brown & Graves, 2013), raised the need to understand the effect of cannabinoids on the placenta. Cannabidiol (CBD) is one of the most abundant cannabinoids in the marijuana plant (Mechoulam & Shvo, 1963; Mechoulam & Hanus, 2002; Schier et al, 2012). It is a promising candidate for clinical utilization, due to low affinity binding to CB1 and CB2 cannabinoid receptors and no cognitive and psychoactive activity (Zuardi, 2008; Deiana, 2012)
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