Characterization and tissue localization of zebrafish homologs of the human<i>ABCB1</i>multidrug transporter

Robey, Robert W.; Robinson, Andrea N.; Ali-Rahmani, Fatima; Huff, Lyn M.; Lusvarghi, Sabrina; Vahedi, Shahrooz; Hotz, Jordan M.; Warner, Andrew C.; Butcher, Donna; Matta, Jennifer; Edmondson, Elijah F.; Lee, Tobie D.; Roth, Jacob S.; Lee, Olivia W.; Shen, Min; Tanner, Kandice; Hall, Matthew D.; Ambudkar, Suresh V.; Gottesman, Michael M.

doi:10.1101/2021.02.18.431829

Cited by 3 publications

(10 citation statements)

References 30 publications

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“…Amino acid sequence comparison between Ta-ABCB1 and vertebrate ABCB1 orthologs (Fig. 1, inserts) shows 74% sequence identity to ABCB4 of model fish species D. rerio and only 53% sequence identity to D. rerio ABCB5, the two identified P-glycoproteins in zebrafish (Fischer et al, 2013;Gordon et al, 2019;Robey et al, 2021). Interestingly Southern Platyfish (X. maculatus) ABCB1/4 had 80.1% sequence identity to Ta-ABCB1.…”

Section: Phylogenetic Analysis Of Ta-abcb1mentioning

confidence: 99%

Transporter-interfering chemicals inhibit P-glycoprotein of yellowfin tuna (Thunnus albacares)

Nicklisch

Pouv

Rees

et al. 2021

Comparative Biochemistry and Physiology Part C: Toxicology &

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Marine pollutants bioaccumulate at high trophic levels of marine food webs and are transferred to humans through consumption of apex species. Yellowfin tuna (Thunnus albacares) are marine predators, and one of largest commercial fisheries in the world. Previous studies have shown that yellowfin tuna can accumulate high levels of persistent organic pollutants, including Transporter Interfering Chemicals (TICs), which are chemicals shown to bind to mammalian xenobiotic transporters and interfere with their function. Here, we examined the extent to which these same compounds might interfere with the activity of the yellowfin tuna (Thunnus albacares) ortholog of this transporter. To accomplish this goal we identified, expressed, and functionally assayed tuna ABCB1. The results demonstrated a common mode of vertebrate ABCB1 interaction with TICs that predicts effects across these species, based on high conservation of specific interacting residues. Importantly several TICs showed potent inhibition of Ta-ABCB1, such as the organochlorine pesticides Endrin (EC 50 = 1.2 ± 0.2 μM) and Mirex (EC 50 = 2.3 ± 0.9 μM). However, unlike the effects observed on mouse ABCB1, low concentrations of the organochlorine pesticide TICs p,p'-DDT and its metabolite p,p'-DDD co-stimulated verapamil-induced Ta-ABCB1 ATPase activity possibly suggesting a low transport activity for these ligands in tuna. These results provide a mechanistic basis for understanding the potential vulnerability of tuna to these ubquitous pollutants.

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Section: Phylogenetic Analysis Of Ta-abcb1mentioning

confidence: 99%

Transporter-interfering chemicals inhibit P-glycoprotein of yellowfin tuna (Thunnus albacares)

Nicklisch

Pouv

Rees

et al. 2021

Comparative Biochemistry and Physiology Part C: Toxicology &

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“…In preliminary studies with HEK293 cells transfected with empty vector (Vector), or with vectors encoding human ABCG2 (R5), zebrafish abcg2a (ZF Abcg2a), zebrafish abcg2b (ZF Abcg2b), zebrafish abcg2c (ZF Abcg2c), or zebrafish abcg2d (ZF Abcg2d), we noted very different substrate specificities in the zebrafish homologs as compared to human ABCG2. As shown in Figure 4, all of the zebrafish forms conferred similar levels of resistance to the known ABCG2 substrates THZ531, THZ1 [83] , and gedatolisib [81] . However, stark differences were noted for mitoxantrone, SN-38 and topotecan, as only Abcg2a and Abcg2d conferred appreciable resistance to mitoxantrone or SN-38, and none of the zebrafish homologs conferred resistance to topotecan.…”

Section: Potential Problems With the Zebrafish Modelmentioning

confidence: 99%

“…Since these results pointed to a difference in substrate specificity between the zebrafish homologs, we performed a high-throughput screen on the transfected cells using 90 substrates of P-gp [ 81 ] . By comparing the drug response area under the curve for cells transfected with empty vector and the different transporters, we found that the substrate specificity profile of zebrafish Abcb4 is similar to that of human P-gp [ 82 ] . Additionally, we found that the efficacy of human P-gp inhibitors varied for zebrafish Abcb4 and Abcb5 and depended on the substrate examined.…”

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

confidence: 99%

“…Using RNAScope in situ probes, we noted that zebrafish abcb4 colocalized with C219 staining in the zebrafish brain vasculature. Vessels in the zebrafish brain that were claudin-5 positive also stained positively with abcb4 probes [ 82 ] . These results support the hypothesis that zebrafish Abcb4 is the functional homolog of human P-gp at the zebrafish BBB.…”

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

confidence: 99%

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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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“…Fish Abcb5 has a different function than the mammalian protein. It is another apical solute transporter related to xenobiotic efflux ( Kropf et al, 2020 ; Robey et al, 2021 ). The zebrafish bile acid cyprinol sulfate induces the transcription of abcb5 in zebrafish liver ( Reschly et al, 2007 ), suggesting potential roles of Abcb5 related to biliary excretion.…”

Section: Abc Proteinsmentioning

confidence: 99%

Expression and Function of ABC Proteins in Fish Intestine

et al. 2021

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In fish, the intestine is fundamental for digestion, nutrient absorption, and other functions like osmoregulation, acid-base balance, and excretion of some metabolic products. These functions require a large exchange surface area, which, in turn, favors the absorption of natural and anthropogenic foreign substances (xenobiotics) either dissolved in water or contained in the food. According to their chemical nature, nutrients, ions, and water may cross the intestine epithelium cells’ apical and basolateral membranes by passive diffusion or through a wide array of transport proteins and also through endocytosis and exocytosis. In the same way, xenobiotics can cross this barrier by passive diffusion or taking advantage of proteins that transport physiological substrates. The entry of toxic substances is counterbalanced by an active efflux transport mediated by diverse membrane proteins, including the ATP binding cassette (ABC) proteins. Recent advances in structure, molecular properties, and functional studies have shed light on the importance of these proteins in cellular and organismal homeostasis. There is abundant literature on mammalian ABC proteins, while the studies on ABC functions in fish have mainly focused on the liver and, to a minor degree, on the kidney and other organs. Despite their critical importance in normal physiology and as a barrier to prevent xenobiotics incorporation, fish intestine’s ABC transporters have received much less attention. All the ABC subfamilies are present in the fish intestine, although their functionality is still scarcely studied. For example, there are few studies of ABC-mediated transport made with polarized intestinal preparations. Thus, only a few works discriminate apical from basolateral transport activity. We briefly describe the main functions of each ABC subfamily reported for mammals and other fish organs to help understand their roles in the fish intestine. Our study considers immunohistochemical, histological, biochemical, molecular, physiological, and toxicological aspects of fish intestinal ABC proteins. We focus on the most extensively studied fish ABC proteins (subfamilies ABCB, ABCC, and ABCG), considering their apical or basolateral location and distribution along the intestine. We also discuss the implication of fish intestinal ABC proteins in the transport of physiological substrates and aquatic pollutants, such as pesticides, cyanotoxins, metals, hydrocarbons, and pharmaceutical products.

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Characterization and tissue localization of zebrafish homologs of the humanABCB1multidrug transporter

Cited by 3 publications

References 30 publications

Transporter-interfering chemicals inhibit P-glycoprotein of yellowfin tuna (Thunnus albacares)

Transporter-interfering chemicals inhibit P-glycoprotein of yellowfin tuna (Thunnus albacares)

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

Expression and Function of ABC Proteins in Fish Intestine

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