Anandamide down-regulates placental transporter expression through CB2 receptor-mediated inhibition of cAMP synthesis. (March 2019)

• Record Type: Journal Article
• Authors: Szilagyi, John T.; Composto-Wahler, Gabriella M.; Joseph, Laurie B.; Wang, Bingbing; Rosen, Todd; Laskin, Jeffrey D.; Aleksunes, Lauren M.
• Is Part Of: Pharmacological research. Volume 141(2019)
• Page Start: 331
• Page End: 342
• Publication Date: 2019-03
• Subjects: ABC ATP-binding cassette -- AEA anandamide -- AKT protein kinase B -- ALP alkaline phosphatase -- BCRP breast cancer resistance protein -- cAMP cyclic adenosine monophosphate -- CB cannabinoid receptor -- CREB cAMP response element binding protein -- DAB 33'-diaminobenzidine -- ERK extracellular signal–regulated kinases -- JNK c-Jun N-terminal kinase -- FAAH fatty acid amide hydrolase -- hCG human choriogonadotropin -- HELLP hemolysis elevated liver enzymes, low platelet count -- HIF1α hypoxia inducible factor 1α -- H33342 Hoechst 33342 -- mTOR mammalian target of rapamycin -- NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells -- PFOS perfluorooctanesulfonic acid PFOA, perfluorooctanoic acid -- PI3K phosphatidylinositol-45-bisphosphate 3-kinase -- PKA protein kinase A -- PPAR peroxisome proliferator-activated receptors -- RPL13A ribosomal protein 13A -- TEER transepithelial electrical resistance -- TRPV1 transient receptor potential cation channel subfamily V member 1; Endocannabinoid -- BCRP -- Placenta -- Transporter -- ABCG2 -- Anandamide -- cAMP; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2019.01.002
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: The BCRP/ABCG2 efflux transporter is expressed on the membrane of placental syncytiotrophoblasts and protects the fetus from toxicant exposure. Syncytiotrophoblasts arise from the fusion of cytotrophoblasts, a process negatively regulated by the endocannabinoid, anandamide (AEA). It is unknown whether AEA can influence fetal concentrations of xenobiotics by modulating the expression of transporters in syncytiotrophoblasts. Here, we sought to characterize and identify the mechanism(s) responsible for AEA-mediated down-regulation of the BCRP transporter in human placental explants and BeWo trophoblasts. Treatment of human placental explants with AEA (1 μM, 24 h) reduced hCGα, syncytin-1, and BCRP mRNAs by ˜30%. Similarly, treatment of BeWo trophoblasts with AEA (0–10 μM, 3-24 h) coordinately down-regulated mRNAs for hCGß, syncytin-2, and BCRP. In turn, AEA increased the sensitivity of trophoblasts to the cytotoxicity of mitoxantrone, a known BCRP substrate, and environmental and dietary contaminants including mycoestrogens and perfluorinated chemicals. AEA-treated trophoblasts also demonstrated reduced BCRP transport of the mycoestrogen zearalenone and the diabetes drug glyburide, labeled with BODIPY. The AEA-mediated reduction of BCRP mRNA was abrogated when placental cells were co-treated with AM630, a CB2 receptor inhibitor, or 8-Br-cAMP, a cAMP analog. AEA reduced intracellular cAMP levels in trophoblasts by 75% at 1 h, and completely inhibited forskolin-induced phosphorylation of the cAMP response element binding protein (CREB). AEA also decreased p-CREB binding to the BCRP promoter. Taken together, our data indicate that AEA down-regulates placental transporter expression and activity via CB2-cAMP signaling. This novel mechanism may explain the repression of placental BCRP expression observed during diseases of pregnancy.