Anandamide down-regulates placental transporter expression through CB2 receptor-mediated inhibition of cAMP synthesis.
ATP Binding Cassette Transporter, Subfamily G, Member 2
/ genetics
Adult
Arachidonic Acids
/ pharmacology
Cannabinoid Receptor Agonists
/ pharmacology
Cell Line
Cyclic AMP
/ metabolism
Down-Regulation
/ drug effects
Endocannabinoids
/ pharmacology
Female
Humans
Neoplasm Proteins
/ genetics
Placenta
/ cytology
Polyunsaturated Alkamides
/ pharmacology
Pregnancy
Receptor, Cannabinoid, CB2
/ metabolism
Signal Transduction
/ drug effects
Trophoblasts
/ cytology
Young Adult
ABCG2
Anandamide
BCRP
Endocannabinoid
Placenta
Transporter
cAMP
Journal
Pharmacological research
ISSN: 1096-1186
Titre abrégé: Pharmacol Res
Pays: Netherlands
ID NLM: 8907422
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
08
10
2018
revised:
01
01
2019
accepted:
01
01
2019
pubmed:
6
1
2019
medline:
24
8
2019
entrez:
6
1
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30610963
pii: S1043-6618(18)31544-5
doi: 10.1016/j.phrs.2019.01.002
pmc: PMC6391190
mid: NIHMS1518832
pii:
doi:
Substances chimiques
ABCG2 protein, human
0
ATP Binding Cassette Transporter, Subfamily G, Member 2
0
Arachidonic Acids
0
Cannabinoid Receptor Agonists
0
Endocannabinoids
0
Neoplasm Proteins
0
Polyunsaturated Alkamides
0
Receptor, Cannabinoid, CB2
0
Cyclic AMP
E0399OZS9N
anandamide
UR5G69TJKH
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Pagination
331-342Subventions
Organisme : NIEHS NIH HHS
ID : R01 ES020522
Pays : United States
Organisme : NIEHS NIH HHS
ID : T32 ES007148
Pays : United States
Organisme : NIEHS NIH HHS
ID : P30 ES005022
Pays : United States
Organisme : NIAMS NIH HHS
ID : U54 AR055073
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES029275
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Ltd. All rights reserved.
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