Xenobiotic transporter activity in zebrafish embryo ionocytes

Gordon, Wei E.; Espinoza, Jose A.; Leerberg, Dena M.; Yelon, Deborah; Hamdoun, Amro

doi:10.1016/j.aquatox.2019.04.013

Cited by 18 publications

(24 citation statements)

References 53 publications

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“…These small molecule transporters (SMTs) are expressed at environmental barriers such as the epithelial cells lining the gut, where they can export toxic compounds for excretion [9,10]. They are also highly expressed in stem cells and embryos [11][12][13][14][15][16][17].…”

Section: Introduction-evolution and Function Of The Small Molecule Trmentioning

confidence: 99%

Disruption of small molecule transporter systems by Transporter‐Interfering Chemicals (TICs)

Nicklisch

Hamdoun

2020

FEBS Letters

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Small molecule transporters (SMTs) in the ABC and SLC families are important players in disposition of diverse endo-and xenobiotics. Interactions of environmental chemicals with these transporters were first postulated in the 1990s, and since validated in numerous in vitro and in vivo scenarios. Recent results on the co-crystal structure of ABCB1 with the flame-retardant BDE-100 demonstrate that a diverse range of man-made and natural toxic molecules, hereafter termed transporter-interfering chemicals (TICs), can directly bind to SMTs and interfere with their function. TIC-binding modes mimic those of substrates, inhibitors, modulators, inducers, and possibly stimulants through direct and allosteric mechanisms. Similarly, the effects could directly or indirectly agonize, antagonize or perhaps even prime the SMT system to alter transport function. Importantly, TICs are distinguished from drugs and pharmaceuticals that interact with transporters in that exposure is unintended and inherently variant. Here, we review the molecular mechanisms of environmental chemical interaction with SMTs, the methodological considerations for their evaluation, and the future directions for TIC discovery.

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Section: Introduction-evolution and Function Of The Small Molecule Trmentioning

confidence: 99%

Disruption of small molecule transporter systems by Transporter‐Interfering Chemicals (TICs)

Nicklisch

Hamdoun

2020

FEBS Letters

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“…This study provided also evidence for the localization of zebrafish Abcb4 in the epidermis, where it could mediate the efflux of chemicals from the embryo [8]. There is indication that ionocytes in the epidermis, which attain particularly high efflux transporter activity, may serve as gateways for the expulsion of chemicals from zebrafish embryos [10]. Although knockdown of zebrafish Abcb5 expression in the embryos did not indicate that this transporter mediates efflux of ABCB1 substrates from the embryo [8], high expression and activity of Abcb5 in ionocytes suggest that Abcb5 allows efflux of certain chemicals across the epidermis [10].…”

Section: Chemical Cas Mw Logp Water Sol (µM) Usagementioning

confidence: 92%

“…In the study presented here, we developed a standardized assay for the quantitative measurement of the fluorescence of accumulated rhodamine B in the yolk sac of live zebrafish embryos. It thus is possible to determine the effects of chemical compounds on ABC efflux transporter activity in native tissue, thus eliminating both dye extraction steps for fluorometric measurements as in earlier protocols [8,11,18] and manual positioning of the embryo under the microscope [10]. This new protocol was first validated with cyclosporin A, verapamil and MK571, which are standard efflux transporter inhibitors [6,19,20] that also interact with zebrafish Abcb4 (Figure 2f, l, s; [8]).…”

Section: Accepted Articlementioning

confidence: 99%

“…There is indication that ionocytes in the epidermis, which attain particularly high efflux transporter activity, may serve as gateways for the expulsion of chemicals from zebrafish embryos [10]. Although knockdown of zebrafish Abcb5 expression in the embryos did not indicate that this transporter mediates efflux of ABCB1 substrates from the embryo [8], high expression and activity of Abcb5 in ionocytes suggest that Abcb5 allows efflux of certain chemicals across the epidermis [10]. Fluorescent dyes acting as transporter substrates that are taken up from the water by aquatic animals can be used to visualize the action of MXR efflux transporters: Fluorescence of the tissue is low when the transporters are active, whereas it increases when the transporter function is reduced (e.g., ref.…”

Section: Chemical Cas Mw Logp Water Sol (µM) Usagementioning

confidence: 99%

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Chemical effects on dye efflux activity in live zebrafish embryos and on zebrafish Abcb4 ATPase activity

et al. 2020

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ATP‐binding cassette (ABC) transporter proteins include efflux pumps that confer multixenobiotic resistance to zebrafish embryos, a valuable toxico/pharmacological model. Here, we established an automated microscopy‐based rhodamine B dye accumulation assay in which enhanced dye accumulation in live zebrafish embryos indicates inhibition of multixenobiotic efflux transporter activity. Twenty structurally divergent known substrates and/or inhibitors of human ABC transporters and environmentally relevant compounds were examined using this assay and the ATPase activity of recombinant zebrafish Abcb4 as readouts. These two assays confirmed that Abcb4 functions as an efflux transporter in zebrafish, whereas they gave discordant results for some of the tested substances. The dye accumulation assay in zebrafish embryos could be useful to screen environmental pollutants and other chemicals for efflux transporter interaction in a medium‐throughput fashion.

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“…Preliminary studies demonstrated that transporters expressed at the zebrafish BBB are able to efflux known P-gp substrates such as rhodamine 123, loperamide and some tyrosine kinase inhibitors [11,17]. Both Abcb4 and Abcb5 have been shown to transport some substrates of human P-gp [15,18,19]; however, detailed substrate specificity testing of the two transporters has not been performed. Here, we provide a detailed characterization of the zebrafish homologs of human ABCB1.…”

Section: Introductionmentioning

confidence: 99%

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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Xenobiotic transporter activity in zebrafish embryo ionocytes

Cited by 18 publications

References 53 publications

Disruption of small molecule transporter systems by Transporter‐Interfering Chemicals (TICs)

Disruption of small molecule transporter systems by Transporter‐Interfering Chemicals (TICs)

Chemical effects on dye efflux activity in live zebrafish embryos and on zebrafish Abcb4 ATPase activity

Characterization and tissue localization of zebrafish homologs of the humanABCB1multidrug transporter

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