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

Marić, Petra; Marijan, Ahel; Nikola, Maraković; Jovica, Lončar; Ivan, Mihaljević; Tvrtko, Smital (2021) Selective interaction of microcystin congeners with zebrafish (Danio rerio) Oatp1d1 transporter. Chemosphere, 283 (131155). pp. 1-12. ISSN 0045-6535

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Abstract

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 IC50 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. Therefore, our study showed that Oatp1d1-mediated transport of MCs could be largely dependent on their basic physicochemical properties, with log POW 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.

Item Type:	Article
Uncontrolled Keywords:	microcystins; zebrafish Oatp1d1; kinetics determinations; substrates vs. inhibitors; chemicaly analytical determinations; molecular docking
Subjects:	NATURAL SCIENCES > Biology > General Biology NATURAL SCIENCES > Interdisciplinary Natural Sciences > Environmental Science
Divisions:	Division for Marine and Enviromental Research
Projects:	Project title Project leader Project code Project type Razumijevanje (eko)toksikološke uloge odabranih SLC i MATE transportnih proteina zebrice (Danio rerio) korištenjem metoda funkcionalne genomike-DANIOTRANS Tvrtko Smital IP-2019-04-1147 HRZZ Ecotoxicological characterization of biologically active substances and complex marine environment samples – projekt u okviru Znanstvenog centra izvrsnosti za znanost i tehnologiju – integracija mediteranske regije (ZCI STIM-REI; https://stim.unist.hr/hr/) (2017-2021) – projekt financiran putem EU kroz Fond za regionalni razvoj, Operativni program konkurentnosti i kohezija (KK.01.1.1.01) Tvrtko Smital KK.01.1.1.01.0003 EK
Depositing User:	Tvrtko Smital
Date Deposited:	06 Dec 2022 14:00
URI:	http://fulir.irb.hr/id/eprint/7689
DOI:	10.1016/j.chemosphere.2021.131155

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