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

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.

Cannabis and anticancer drugs: societal usage and expected pharmacological interactions – a review

“…These results are confirmed by other studies, in particular an ex vivo study carried out on samples of human placenta . However, the impact of cannabinoids on the modulation of BCRP gene expression is not clear, as the studies are contradictory .…”

Cannabinoids, Blood–Brain Barrier, and Brain Disposition

“…It has been found that CBD, being a THC isomer, reduces P-gp and Bcrp transport, although this effect was found to be less congruous for the transporter P-gp [95]. In this regard, since inhibitors are often substrates, it is necessary to clarify if CBD is a substrate for one (P-gp) or both transporters (P-gp and Bcrp), and how this affinity influences brain crossing and delivery of this cannabinoid.…”

Is cannabidiol a drug acting on unconventional targets to control drug‐resistant epilepsy?

“…Studies indicate that CBD down‐regulates the protein and mRNA expression of P‐glycoprotein and inhibits its efflux function in trophoblast cell lines . CBD also interacts with a specific site of the P‐glycoprotein interfering with the ATPase activity stimulated by substrates and consequently decreasing the energy required for their transport in Caco‐2 and LLC‐PK1/MDR1 cells .…”

“…111,114,115 Studies indicate that CBD down-regulates the protein and mRNA expression of P-glycoprotein and inhibits its efflux function in trophoblast cell lines. 116 CBD also interacts with a specific site of the P-glycoprotein interfering with the ATPase activity stimulated by substrates and consequently decreasing the energy required for their transport in Caco-2 and LLC-PK1/MDR1 cells. 117 The inhibitory effect of CBD on P-glycoprotein is evident after prolonged, but not shortterm exposure, in cells CEM/VLB 100 that overexpress this transporter.…”