Selective interaction of microcystin congeners with zebrafish (Danio rerio) Oatp1d1 transporter.

Autor: Marić P; Laboratory for Molecular Ecotoxicology, Division for Marine and Environmental Research, Ruđer Bošković Institute, Bijenička 54, Zagreb, Croatia., Ahel M; Laboratory for Analytical Chemistry and Biogeochemistry of Organic Compounds, Division for Marine and Environmental Research, Ruđer Bošković Institute, Bijenička 54, 10000, Zagreb, Croatia., Maraković N; Institute for Medical Research and Occupational Health, Ksaverska Cesta 2, 10000, Zagreb, Croatia., Lončar J; Laboratory for Molecular Ecotoxicology, Division for Marine and Environmental Research, Ruđer Bošković Institute, Bijenička 54, Zagreb, Croatia., Mihaljević I; Laboratory for Molecular Ecotoxicology, Division for Marine and Environmental Research, Ruđer Bošković Institute, Bijenička 54, Zagreb, Croatia., Smital T; Laboratory for Molecular Ecotoxicology, Division for Marine and Environmental Research, Ruđer Bošković Institute, Bijenička 54, Zagreb, Croatia. Electronic address: smital@irb.hr.
Jazyk: angličtina
Zdroj: Chemosphere [Chemosphere] 2021 Nov; Vol. 283, pp. 131155. Date of Electronic Publication: 2021 Jun 10.
DOI: 10.1016/j.chemosphere.2021.131155
Abstrakt: Microcystins (MCs) are the most studied cyanotoxins. The uptake of MCs in cells and tissues of mammals and fish species is mostly mediated by organic anion-transporting polypeptides (OATPs in humans and rodents; Oatps in other species), and the Oatp1d1 appears to be a major transporter for MCs in fish. In this study, six MC congeners of varying physicochemical properties (MC-LR, -RR, -YR, -LW, -LF, -LA) were tested by measuring their effect on the uptake of model Oatp1d1 fluorescent substrate Lucifer yellow (LY) in HEK293T cells transiently or stably overexpressing zebrafish Oatp1d1. MC-LW and -LF showed the strongest interaction resulting in an almost complete inhibition of LY transport with IC 50 values of 0.21 and 0.26 μM, while congeners -LR, -YR and -LA showed lower inhibitory effects. To discern between Oatp1d1 substrates and inhibitors, results were complemented by Michaelis-Menten kinetics and chemical analytical determinations of MCs uptake, along with molecular docking studies performed using the developed zebrafish Oatp1d1 homology model. Our study showed that Oatp1d1-mediated transport of MCs could be largely dependent on their basic physicochemical properties, with log P OW being the most obvious determinant. Finally, apart from determination of the chemical composition of cynobacterial blooms, a reliable risk assessment should take into account the interaction of identified MC congeners with Oatp1d1 as their primary transporter, and herewith we demonstrated that such a comprehensive approach could be based on the use of highly specific in vitro models, accompanied by chemical assessment and in silico molecular docking studies.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: