Environmental contaminants modulate transport activity of zebrafish organic anion transporters Oat1 and Oat3

Dragojević, Jelena; Marić, Petra; Lončar, Jovica; Popović, Marta; Mihaljević, Ivan; Smital, Tvrtko

doi:10.1016/j.cbpc.2020.108742

Cited by 2 publications

(4 citation statements)

References 38 publications

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“…The present study shows that zebrafish oct2 when expressed in Xenopus oocytes can facilitate the transport of ranitidine, propranolol, and TEA (Figures 1-4). This contributes to the knowledge that shows several other zebrafish SLC proteins can transport a wide range of endogenous compounds, including steroids and steroid conjugates, xenobiotic, drugs and their metabolites (Dragojević et al, 2018(Dragojević et al, , 2019(Dragojević et al, , 2020(Dragojević et al, , 2021Lončar et al, 2016;Mihaljević et al, 2017;Popovic et al, 2013), and are likely to play a significant role in ADME processes in fish.…”

Section: Resultsmentioning

confidence: 84%

“…Pharmacokinetics is a particular challenge for NAMs due to the complexity of physiological systems throughout the animal kingdom. In vitro functional data, such as that derived in the present study, and those for a plethora of SLC transport proteins in zebrafish (Dragojević et al, 2018(Dragojević et al, , 2019(Dragojević et al, , 2020(Dragojević et al, , 2021Lončar & Smital, 2018;Lončar et al, 2016;Mihaljević et al, 2017;Popovic et al, 2013), when combined with plasma concentrations, tissue expression and localization data can be used to generate physiologically based PK models for internal distribution. However, for aquatic organisms an important component of bioaccumulation studies is uptake from the water.…”

Section: Resultsmentioning

confidence: 99%

“…Many of these transport proteins are described as being polyspecific, that is, they can interact with compounds of various molecular structures and sizes, thus exhibiting large differences in substrate turnover and affinity that can transfer several endogenous compounds, xenobiotics, and metabolites in addition to drugs (Koepsell, 2021). A wide range of chemical substrates have been shown for the zebrafish slc22a6 and 8 (Dragojević et al, 2019(Dragojević et al, , 2020, slc22a1 (Mihaljević et al, 2017), and members of the slc47 family (Lončar & Smital, 2018;Lončar et al, 2016) when expressed in mammalian cell lines. These transport proteins play a key role in chemical and drug absorption, distribution, metabolism, and excretion (ADME) processes (Koepsell, 2020(Koepsell, , 2021.…”

Section: Introductionmentioning

confidence: 99%

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Active Pharmaceutical Ingredient Uptake by Zebrafish (Danio rerio) Oct2 (slc22a2) Transporter Expressed in Xenopus laevis Oocytes

Chang

Owen

Högstrand

et al. 2022

Enviro Toxic and Chemistry

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Uptake of active pharmaceutical ingredients (APIs) across the gill epithelium of fish is via either a passive or facilitated transport process, with the latter being more important at the lower concentrations more readily observed in the environment. The solute carrier (SLC) 22A family, which includes the organic cation transporter OCT2 (SLC22A2), has been shown in mammals to transport several endogenous chemicals and APIs. Zebrafish oct2 was expressed in Xenopus oocytes and the uptake of ranitidine, propranolol, and tetraethylammonium characterized. Uptake of ranitidine and propranolol was time-and concentration-dependent with a k m and V max for ranitidine of 246 µM and 45 pmol/(oocyte × min) and for propranolol of 409 µM and 190 pmol/(oocyte × min), respectively. Uptake of tetraethylammonium (TEA) was inhibited by propranolol, amantadine, and cimetidine, known to be human OCT2 substrates, but not quinidine or ranitidine. At external media pH 7 and 8 propranolol uptake was 100-fold greater than at pH 6; pH did not affect ranitidine or TEA uptake. It is likely that cation uptake is driven by the electrochemical gradient across the oocyte. Uptake kinetics parameters, such as those derived in the present study, coupled with knowledge of transporter localization and abundance and API metabolism, can help derive pharmacokinetic models.

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Section: Resultsmentioning

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Active Pharmaceutical Ingredient Uptake by Zebrafish (Danio rerio) Oct2 (slc22a2) Transporter Expressed in Xenopus laevis Oocytes

Chang

Owen

Högstrand

et al. 2022

Enviro Toxic and Chemistry

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“…Zebrafish Oats, including Oat1 and Oat3, play an important role in modulating the transport activity of PFOS. Specifically, zebrafish Oat1 and Oat3 exhibit interactions with environmental contaminants, including PFOS, affecting their bioavailability and toxicity in zebrafish (Dragojević et al, 2020). Oatp1d1 has a high affinity towards PFOS.…”

Section: Introductionmentioning

confidence: 99%

Differential Toxicity of Perfluorooctane Sulfonate (PFOS) in Wild-Type and Oatp1d1 Mutant Zebrafish Embryos

Mihaljevic,

Vujica,

Dragojević

et al. 2024

Preprint

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This study presents a comprehensive analysis of the effects of perfluorooctane sulfonate (PFOS) exposure on zebrafish embryos, focusing on the differential responses between wild-type (WT) and oatp1d1 mutant embryos. The findings improve our understanding of the toxicokinetic and toxicodynamic mechanisms of PFOS, a persistent and bioaccumulative member of the per- and polyfluoroalkyl substances (PFAS) family. The study revealed significant differences in mortality rates with calculated LC50 values of 23.57 µM for WT and 16.71 µM for oatp1d1 mutants, indicating a higher susceptibility of the mutants to PFOS toxicity. This indicates the crucial role of the Oatp1d1 transporter in mediating the toxic effects of PFOS, possibly related to detoxification processes or regulation of bioavailability. Developmental abnormalities, particularly in the swim bladder, were more pronounced in mutant embryos, indicating the role of the transporter in mitigating PFOS-induced developmental toxicity. Gene expression analysis showed differential modulation of biotransformation genes, including cytochrome P450 (cyp) and glutathione S-transferase (gst) genes, underscoring the complexity of PFOS toxicity. The study also highlighted disruptions in lipid metabolism with altered expression of genes involved in lipid synthesis and oxidation, leading to abnormal lipid accumulation. These findings have significant implications for aquatic ecosystems and human health, as PFOS is persistent and bioaccumulative in the environment. The study emphasizes the need for stringent regulatory measures and effective remediation strategies to address PFOS contamination and protect both aquatic life and human populations.

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Environmental contaminants modulate transport activity of zebrafish organic anion transporters Oat1 and Oat3

Cited by 2 publications

References 38 publications

Active Pharmaceutical Ingredient Uptake by Zebrafish (Danio rerio) Oct2 (slc22a2) Transporter Expressed in Xenopus laevis Oocytes

Active Pharmaceutical Ingredient Uptake by Zebrafish (Danio rerio) Oct2 (slc22a2) Transporter Expressed in Xenopus laevis Oocytes

Differential Toxicity of Perfluorooctane Sulfonate (PFOS) in Wild-Type and Oatp1d1 Mutant Zebrafish Embryos

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