Interindividual Regulation of the Breast Cancer Resistance Protein/<i>ABCG2</i>Transporter in Term Human Placentas

Bircsak, Kristin M.; Moscovitz, Jamie E.; Wen, Xiaozhong; Archer, Faith; Yuen, Poi Yu Sofia; Mohammed, Moiz; Memon, Naureen; Weinberger, Barry; Saba, Laura; Vetrano, Anna M.; Aleksunes, Lauren M.

doi:10.1124/dmd.117.079228

Cited by 26 publications

(21 citation statements)

References 41 publications

(23 reference statements)

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“…There exist genetic, pathological, and toxicological factors that decrease placental BCRP activity and may therefore increase fetal exposure to zearalenone. The 421C > A (Q141K) BCRP polymorphism, for instance, significantly decreases BCRP protein expression (40%-50%) but not transcription (Bircsak et al, 2018). The 421C > A allele varies between ethnic groups, but is relatively common among Asian (32%) and Hispanic (28%) populations (Bircsak et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…The 421C > A (Q141K) BCRP polymorphism, for instance, significantly decreases BCRP protein expression (40%-50%) but not transcription (Bircsak et al, 2018). The 421C > A allele varies between ethnic groups, but is relatively common among Asian (32%) and Hispanic (28%) populations (Bircsak et al, 2018). Previous in vitro experiments with Q141K BCRP expressing human embryonic kidney cells demonstrate increased retention of H33342, glyburide, and zearalenone compared with those expressing wild-type BCRP protein (Bircsak et al, 2016;Xiao et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

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Placental BCRP/ABCG2Transporter Prevents Fetal Exposure to the Estrogenic Mycotoxin Zearalenone

Szilagyi

Gorczyca

Brinker

et al. 2018

Toxicological Sciences

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In the placenta, the breast cancer resistance protein (BCRP)/ABCG2 efflux transporter limits the maternal-to-fetal transfer of drugs and chemicals. Previous research has pointed to the estrogenic mycotoxin zearalenone as a potential substrate for BCRP. Here, we sought to assess the role of the BCRP transporter in the transplacental disposition of zearalenone during pregnancy. In vitro transwell transport assays employing BCRP/Bcrp-transfected Madine-Darby canine kidney cells and BeWo trophoblasts with reduced BCRP expression were used to characterize the impact of BCRP on the bidirectional transport of zearalenone. In both models, the presence of BCRP protein increased the basolateral-to-apical transport and reduced the apical-to-basolateral transport of zearalenone over a 2-h period. In vivo pharmacokinetic analyses were then performed using pregnant wild-type and Bcrp À/À mice after a single tail vein injection of zearalenone. Zearalenone and its metabolite a-zearalenol were detectable in serum, placentas, and fetuses from all animals, and b-zearalenol was detected in serum and fetuses, but not placentas. There were no significant differences in the maternal serum concentrations of any analytes between the two genotypes. In Bcrp À/À mice, the free fetal concentrations of zearalenone, a-zearalenol, and bzearalenol were increased by 115%, 84%, and 150%, respectively, when compared with wild-type mice. Concentrations of free zearalenone and a-zearalenol were elevated 145% and 78% in Bcrp À/À placentas, respectively, when compared with wild-type placentas. Taken together, these data indicate that the placental BCRP transporter functions to reduce the fetal accumulation of zearalenone, which may impact susceptibility to developmental toxicities associated with in utero zearalenone exposure.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Placental BCRP/ABCG2Transporter Prevents Fetal Exposure to the Estrogenic Mycotoxin Zearalenone

Szilagyi

Gorczyca

Brinker

et al. 2018

Toxicological Sciences

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“…Staining results indicate that the transporter is expressed in the apical membrane of the syncytiotrophoblasts and cytotrophoblasts as well as in fetal endothelial cells from the first trimester to term . Various studies have quantified the expression of BCRP relative to the expression of housekeeping genes such as GAPDH, HPRT, YWHAZ, β‐actin , and 18S . Although no clear pattern emerges from these studies, BCRP expression seems to decrease or remain unchanged between the first trimester and term …”

Section: Placental Transportersmentioning

confidence: 99%

“…23,25,[33][34][35][36][37] Various studies have quantified the expression of BCRP relative to the expression of housekeeping genes such as GAPDH, HPRT, YWHAZ, β-actin, and 18S. 23,[25][26][27][28]33,36,[38][39][40][41][42][43][44] Although no clear pattern emerges from these studies, BCRP expression seems to decrease or remain unchanged between the first trimester and term. 23,[25][26][27][28]39,43 Organic Anion Transporter 1.…”

Section: Expression and Ontogeny Of Placental Transportersmentioning

confidence: 99%

Drug Transporters Expressed in the Human Placenta and Models for Studying Maternal‐Fetal Drug Transfer

Dallmann

Liu

Burckart

et al. 2019

The Journal of Clinical Pharma

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Tremendous efforts have been directed to investigate the ontogeny of drug transporters in fetuses, neonates, infants, and children based on their importance for understanding drug pharmacokinetics. During development (ie, in the fetus and newborn infant), there is special interest in transporters expressed in the placenta that modulate placental drug transfer. Many of these transporters can decrease or increase drug concentrations in the fetus and at birth, stressing the relevance of elucidating expression in the placenta and potential gestational age‐dependent changes therein. Hence, the main objective of this review was to summarize the current knowledge about expression and ontogeny of transporters in the human placenta in healthy pregnant women. In addition, various in vitro, ex vivo, and in silico models that can be used to investigate placental drug transfer, namely, placental cancer cell lines, ex vivo cotyledon perfusion experiments, and physiologically based pharmacokinetic (PBPK) models, are discussed together with their advantages and shortcomings. A particular focus was placed on PBPK models because these models can integrate different types of information, such as expression data, ontogeny information, and observations obtained from the ex vivo cotyledon perfusion experiment. Such a mechanistic modeling framework may leverage the available information and ultimately help to improve knowledge about the adequacy and safety of pharmacotherapy in pregnant women and their fetuses.

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“…The FDA accepted BCRP as a key drug transporter involved in clinically relevant DDIs, adverse drug reactions, and therapeutic failure of drugs due to its localization in organs that are important in drug disposition [5,6]. Unpredictable drug effects due to alterations in BCRP expression and activity have been frequently observed during clinical therapy [7][8][9]. Therefore, it is of great clinical importance to elucidate the molecular mechanisms underlying the regulation of BCRP expression.…”

Section: Introductionmentioning

confidence: 99%

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

Zhang

Huang

et al. 2020

Genes

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Breast cancer resistance protein (BCRP), an ATP-binding cassette (ABC) half transporter encoded by the Abcg2 gene, is reported to influence the pharmacokinetics of substrate drugs during clinical therapy. The aim of this study was to clarify the mechanisms that regulate the transcription of the chicken Abcg2 gene through cloning and characterization of its promoter region. Results showed that the Abcg2 gene is transcribed by a TATA-less promoter with several putative Sp1 sites upstream from two putative CpG islands. A luciferase reporter assay conducted both in chicken leghorn male hepatoma (LMH) cells and chicken primary hepatocytes mapped a basal promoter to nucleotides −110 to +30, which is responsible for the constitutive expression of Abcg2. The 5′-region upstream of the basal promoter was characterized by both positive and negative regulatory domains. Further, using the cell-based reporter gene assay combined with RT-PCR and drug accumulation analysis, we found that four xenobiotics, daidzein, clotrimazole, ivermectin, and lipopolysaccharide (LPS), influence the expression and function of BCRP through significant regulation of the Abcg2 gene promoter. Interaction sites with the Abcg2 gene promoter of these four selected regulators were clarified by progressive deletions and mutation assays. This study shed some light on the regulatory mechanisms involved in chicken Abcg2 gene expression and the results may have far-reaching significance regarding the usage and development of veterinary drugs.

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Interindividual Regulation of the Breast Cancer Resistance Protein/ABCG2Transporter in Term Human Placentas

Cited by 26 publications

References 41 publications

Placental BCRP/ABCG2Transporter Prevents Fetal Exposure to the Estrogenic Mycotoxin Zearalenone

Placental BCRP/ABCG2Transporter Prevents Fetal Exposure to the Estrogenic Mycotoxin Zearalenone

Drug Transporters Expressed in the Human Placenta and Models for Studying Maternal‐Fetal Drug Transfer

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

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