Zebrafish Abcb4 is a potential efflux transporter of microcystin-LR

Lü, Xing; Long, Yong; Sun, Rongze; Zhou, Bolan; Lin, Li; Zhong, Shan

doi:10.1016/j.cbpc.2014.08.005

Cited by 23 publications

(15 citation statements)

References 42 publications

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“…We found high reactivity with the C219 antibody in the gastrointestinal tract of the zebrafish and found that this was mainly due to high levels of abcb4 expression. This is in agreement with Umans and Taylor who reported C219 staining in the intestinal epithelium of zebrafish larvae {Umans, 2012 #4892} and Lu et al who found high levels of abcb4 gene expression in the intestine of adult zebrafish [29]. The high levels of Abcb4 in the zebrafish gut appear to suggest that the zebrafish could be used in pre-clinical studies to determine the oral bioavailability of drugs.…”

Section: Discussionsupporting

confidence: 88%

Characterization and tissue localization of zebrafish homologs of the humanABCB1multidrug transporter

Robey

Robinson

Ali-Rahmani

et al. 2021

Preprint

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Given its similarities with mammalian systems, the zebrafish has emerged as a potential model to study the blood-brain barrier (BBB). Capillary endothelial cells at the human BBB express high levels of P-glycoprotein (P-gp, encoded by the ABCB1 gene) and ABCG2 (encoded by the ABCG2 gene). However, little information has been available about ATP-binding cassette transporters expressed at the zebrafish BBB. In this study, we focus on the characterization and tissue localization of two genes that are similar to human ABCB1, zebrafish abcb4 and abcb5. Cytotoxicity assays with stably-transfected cell lines revealed that zebrafish Abcb5 cannot efficiently transport the substrates doxorubicin and mitoxantrone compared to human P-gp and zebrafish Abcb4. Additionally, zebrafish Abcb5 did not transport the fluorescent probes BODIPY-ethylenediamine or LDS 751, while they were readily transported by Abcb4 and P-gp. A high-throughput screen conducted with 90 human P-gp substrates confirmed that zebrafish Abcb4 has overlapping substrate specificity with P-gp. Basal ATPase activity of zebrafish Abcb4 and Abcb5 was comparable to that of human P-gp. In the brain vasculature, RNAscope probes to detect abcb4 colocalized with staining by the P-gp antibody C219, while abcb5 was not detected. Zebrafish abcb4 also colocalized with claudin-5 expression in brain endothelial cells. Abcb4 and Abcb5 had different tissue localizations in multiple zebrafish tissues, consistent with different functions. The data suggest that zebrafish Abcb4 most closely phenocopies P-gp and that the zebrafish may be a viable model to study the role of the multidrug transporter P-gp at the BBB.

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Section: Discussionsupporting

confidence: 88%

Characterization and tissue localization of zebrafish homologs of the humanABCB1multidrug transporter

Robey

Robinson

Ali-Rahmani

et al. 2021

Preprint

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“…Fischer et al [66] examined the accumulation of P-gp substrates rhodamine B and calcein-AM in whole embryo assays and demonstrated increased fluorescence in the embryos treated with the substrates and P-gp inhibitors compared to the embryos treated with the substrates alone. In a subsequent study, a number of compounds were also found to increase rhodamine B fluorescence in embryos at 72 hpf, potentially due to inhibition of zebrafish Abcb4 [79] . The cyanobacterial toxin microcystin-LR was also found to be a substrate of Abcb4 based on cytotoxicity assays with LLC-PK1 cells transfected with zebrafish abcb4 as well as microinjection of zebrafish embryos with abcb4 [80] .…”

Section: Potential Problems With the Zebrafish Modelmentioning

confidence: 88%

“…In a subsequent study, a number of compounds were also found to increase rhodamine B fluorescence in embryos at 72 hpf, potentially due to inhibition of zebrafish Abcb4 [ 79 ] . The cyanobacterial toxin microcystin-LR was also found to be a substrate of Abcb4 based on cytotoxicity assays with LLC-PK1 cells transfected with zebrafish abcb4 as well as microinjection of zebrafish embryos with abcb4 [ 80 ] . Expression of Abcb5 was recently localized to zebrafish ionocytes and the fluorescent P-gp substrates calcein-AM and DiOC6 were transported, demonstrating that Abcb4 and Abcb5 can efflux known P-gp substrates.…”

Section: The Zebrafish As a Model To Study Abc Transporters At The Bbbmentioning

confidence: 99%

ATP-binding cassette transporters at the zebrafish blood-brain barrier and the potential utility of the zebrafish as an in vivo model

Hotz

Thomas

Katz

et al. 2021

CDR

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The brain is protected from toxins by a tightly regulated network of specialized cells, including endothelial cells, pericytes, astrocyes, and neurons, known collectively as the blood-brain barrier (BBB). This selectively permeable barrier permits only the most crucial molecules essential for brain function to enter and employs a number of different mechanisms to prevent the entry of potentially harmful toxins and pathogens. In addition to a physical barrier comprised of endothelial cells that form tight junctions to restrict paracellular transport, there is an active protective mechanism made up of energy-dependent transporters that efflux compounds back into the bloodstream. Two of these ATP-binding cassette (ABC) transporters are highly expressed at the BBB: Pglycoprotein (P-gp, encoded by the ABCB1 gene) and ABCG2 (encoded by the ABCG2 gene). Although a number of in vitro and in vivo systems have been developed to examine the role that ABC transporters play in keeping compounds out of the brain, all have inherent advantages and disadvantages. Zebrafish (Danio rerio) have become a model of interest for studies of the BBB due to the similarities between the zebrafish and mammalian BBB systems. In this review, we discuss what is known about ABC transporters in zebrafish and what information is still needed before the zebrafish can be recommended as a model to elucidate the role of ABC transporters at the BBB.

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“…These genes play important roles in protecting organisms from xenobiotics 58 . It was reported that abcb4 could affect bioavailability of chemicals to zebrafish embryos 58 and adult tissues 59 . The ATP-binding cassette superfamily of genes was also found over-expressed in liver and gill of zebrafish when exposed to uranium 57 .…”

Section: Discussionmentioning

confidence: 99%

Toxicity and Transcriptome Sequencing (RNA-seq) Analyses of Adult Zebrafish in Response to Exposure Carboxymethyl Cellulose Stabilized Iron Sulfide Nanoparticles

Zheng

Lü

2018

Sci Rep

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Increasing utilization of stabilized iron sulfides (FeS) nanoparticles implies an elevated release of the materials into the environment. To understand potential impacts and underlying mechanisms of nanoparticle-induced stress, we used the transcriptome sequencing (RNA-seq) technique to characterize the transcriptomes from adult zebrafish exposed to 10 mg/L carboxymethyl cellulose (CMC) stabilized FeS nanoparticles for 96 h, demonstrating striking differences in the gene expression profiles in liver. The exposure caused significant expression alterations in genes related to immune and inflammatory responses, detoxification, oxidative stress and DNA damage/repair. The complement and coagulation cascades Kyoto encyclopedia of genes and genomes (KEGG) pathway was found significantly up-regulated under nanoparticle exposure. The quantitative real-time polymerase chain reaction using twelve genes confirmed the RNA-seq results. We identified several candidate genes commonly regulated in liver, which may serve as gene indicators when exposed to the nanoparticles. Hepatic inflammation was further confirmed by histological observation of pyknotic nuclei, and vacuole formation upon exposure. Tissue accumulation tests showed a 2.2 times higher iron concentration in the fish tissue upon exposure. This study provides preliminary mechanistic insights into potential toxic effects of organic matter stabilized FeS nanoparticles, which will improve our understanding of the genotoxicity caused by stabilized nanoparticles.

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Zebrafish Abcb4 is a potential efflux transporter of microcystin-LR

Cited by 23 publications

References 42 publications

Characterization and tissue localization of zebrafish homologs of the humanABCB1multidrug transporter

Characterization and tissue localization of zebrafish homologs of the humanABCB1multidrug transporter

ATP-binding cassette transporters at the zebrafish blood-brain barrier and the potential utility of the zebrafish as an in vivo model

Toxicity and Transcriptome Sequencing (RNA-seq) Analyses of Adult Zebrafish in Response to Exposure Carboxymethyl Cellulose Stabilized Iron Sulfide Nanoparticles

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