TY - JOUR T1 - Buprenorphine, Norbuprenorphine, R-Methadone and S-Methadone Upregulate BCRP/ABCG2 Expression by Activating Aryl Hydrocarbon Receptor in Human Placental Trophoblasts JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.116.107367 SP - mol.116.107367 AU - Naveen K Neradugomma AU - Michael Z Liao AU - Qingcheng Mao Y1 - 2016/01/01 UR - http://molpharm.aspetjournals.org/content/early/2016/12/14/mol.116.107367.abstract N2 - 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 pregnancy drug abuse. 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 brought about by these drugs in the placenta. 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 AhR specific antagonist. These drugs increased AhR recruitment onto the AhR-response elements and significantly induced BCRP gene transcription. AhR overexpression further increased BCRP mRNA and protein expression. Knocking down 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 with 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. ER -