Breast Cancer Resistance Protein 1 Limits Fetal Distribution of Nitrofurantoin in the Pregnant Mouse

Zhang, Yi; Wang, Honggang; Unadkat, Jashvant D.; Mao, Qingcheng

doi:10.1124/dmd.107.018044

Cited by 73 publications

(56 citation statements)

References 32 publications

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“…In the placenta, BCRP is located on the apical membrane of syncytiotrophoblasts that faces the maternal blood (Maliepaard et al, 2001), implicating its role in limiting fetal exposure to drugs and xenobiotics by pumping them from the fetal compartment back to the maternal circulation. In vivo studies using Bcrp1 knockout mice have indeed shown that Bcrp1, the murine homolog of human BCRP, significantly limits fetal exposure to certain BCRP substrates including glyburide, nitrofurantoin, and topotecan (Jonker et al, 2000;Zhang et al, 2007;Zhou et al, 2008). Results from placenta perfusion studies support the same conclusion (Kraemer et al, 2006;Staud et al, 2006).…”

Section: Introductionsupporting

confidence: 74%

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

2016

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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.

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Section: Introductionsupporting

confidence: 74%

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

2016

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“…In support of this, glyburide concentrations are higher in Bcrp-null fetuses compared with wild type (Zhou et al, 2008b). Likewise, the concentration of the antibiotic nitrofurantoin is elevated 5-fold in fetuses from Bcrp-null mice (Zhang et al, 2007c). These findings are of interest because glyburide and nitrofurantoin are routinely prescribed for pregnant patients for the treatment of gestational diabetes and urinary tract infections, respectively.…”

mentioning

confidence: 53%

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

2010

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“…We found that fetal exposure (fetal-to-maternal plasma AUC ratios) to nitrofurantoin and glyburide in Bcrp1-knockout mice was increased ∼five-and twofold, respectively, compared to those in wild-type mice (35,113). The role of BCRP in determining fetal exposure to drugs and xenobiotics can also be studied using other methods such as human placenta perfusion, and this topic has been extensively reviewed elsewhere (114).…”

Section: Tissue Localization and Role In Drug Dispositionmentioning

confidence: 98%

Role of the Breast Cancer Resistance Protein (BCRP/ABCG2) in Drug Transport—an Update

Mao

Unadkat

2014

AAPS J

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519

387

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Abstract. The human breast cancer resistance protein (BCRP, gene symbol ABCG2) is an ATP-binding cassette (ABC) efflux transporter. It was so named because it was initially cloned from a multidrugresistant breast cancer cell line where it was found to confer resistance to chemotherapeutic agents such as mitoxantrone and topotecan. Since its discovery in 1998, the substrates of BCRP have been rapidly expanding to include not only therapeutic agents but also physiological substances such as estrone-3-sulfate, 17β-estradiol 17-(β-D-glucuronide) and uric acid. Likewise, at least hundreds of BCRP inhibitors have been identified. Among normal human tissues, BCRP is highly expressed on the apical membranes of the placental syncytiotrophoblasts, the intestinal epithelium, the liver hepatocytes, the endothelial cells of brain microvessels, and the renal proximal tubular cells, contributing to the absorption, distribution, and elimination of drugs and endogenous compounds as well as tissue protection against xenobiotic exposure. As a result, BCRP has now been recognized by the FDA to be one of the key drug transporters involved in clinically relevant drug disposition. We published a highly-accessed review article on BCRP in 2005, and much progress has been made since then. In this review, we provide an update of current knowledge on basic biochemistry and pharmacological functions of BCRP as well as its relevance to drug resistance and drug disposition.

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Breast Cancer Resistance Protein 1 Limits Fetal Distribution of Nitrofurantoin in the Pregnant Mouse

Cited by 73 publications

References 32 publications

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

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

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

Role of the Breast Cancer Resistance Protein (BCRP/ABCG2) in Drug Transport—an Update

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