Buprenorphine, Norbuprenorphine, R-Methadone, and S-Methadone Upregulate BCRP/ABCG2 Expression by Activating Aryl Hydrocarbon Receptor in Human Placental Trophoblasts

Abstract

Opioid dependence during pregnancy is a rising concern. Maintaining addicted pregnant women on long-acting opioid receptor agonist is the most common strategy to manage drug abuse in pregnant women. Methadone (MET) and buprenorphine (BUP) are widely prescribed for opiate maintenance therapy. Norbuprenorphine (NBUP) is the primary active metabolite of BUP. These medications can cross the placenta to the fetus, leading to postpartum neonatal abstinence syndrome. Despite their use during pregnancy, little is known about the cellular changes in the placenta brought about by these drugs. In this study, we showed that BUP, NBUP, and MET at clinically relevant plasma concentrations significantly induced BCRP mRNA up to 10-fold in human model placental JEG3 and BeWo cells and in primary human villous trophoblasts, and this induction was abrogated by CH223191, an aryl hydrocarbon receptor (AhR)-specific antagonist. These drugs increased AhR recruitment onto the AhR-response elements and significantly induced breast cancer resistance protein (BCRP) gene transcription. AhR overexpression further increased BCRP mRNA and protein expression. Knockdown of AhR by shRNA decreased BCRP expression, and this decrease was reversed by rescuing AhR expression. Finally, induction of BCRP expression in JEG3 and BeWo cells was accompanied by an increase in its efflux activity. Collectively, we have demonstrated, for the first time, that BUP, NBUP, and MET are potent AhR agonists and can induce BCRP in human placental trophoblasts by activating AhR. Given the critical role of BCRP in limiting fetal exposure to drugs and xenobiotics, long-term use of these medications may affect fetal drug exposure by altering BCRP expression in human placenta.

Regulation of human placental drug transporters in HCV infection and their influence on direct acting antiviral medications

“…It should be noted that several of the HCV patients reported a history of using drugs of abuse or were prescribed methadone maintenance therapy. A prior report indicated that methadone upregulates BCRP expression in human trophoblasts [24]. However, the HCV samples with the greatest expression levels of BCRP and P-gp were not associated with those patients on methadone maintenance therapy.…”

An update on expression and function of P-gp/ABCB1 and BCRP/ABCG2 in the placenta and fetus

“…While there is a consensus that P-gp levels in human placenta decline with gestational age, controversial results exist regarding the changes of BCRP expression in human placenta over gestation [40,71]. P-gp and BCRP expression in the placenta could be regulated at the transcriptional, translational and post-translational levels [79,83,89,136]. Recent studies indicate that the roles of P-gp (likely BCRP as well) in determining fetal drug exposure depend on drugs administered even if the drugs are their substrates, a phenomenon that could be interpreted by the concept of fraction of drug transported [51,56,57,61,80,91,92,95,137,138].…”

“…Continuous exposure of BeWo cells to genistein (a dietary isoflavone) for 48 hours reduced the expression of ABCG2 mRNA and protein by up to 40%, and the down-regulation could be attenuated by pharmacological inhibition of the estrogen receptor, suggesting that phytoestrogens may reduce BCRP expression through this hormone receptor pathway in BeWo cells [88]. Buprenorphine, norbuprenorphine, and methadone (narcotic), which are potent AhR agonists, can induce BCRP in human placental trophoblasts by activating AhR [89]. Acetaminophen (analgesic) was found to induce oxidative stress and down-regulate BCRP/Bcrp in human JEG-3 cells or rat placenta [90].…”

Identification of Functional Transcriptional Binding Sites within Chicken Abcg2 Gene Promoter and Screening Its Regulators

“…Previous studies suggested that the expression of BCRP is tightly regulated, mainly at the transcriptional level with species-specific induction [28,29]. Promoters, which are usually located upstream of a gene, play a decisive role in gene transcription.…”