Human HepaRG liver spheroids: cold storage protocol and study on pyridinium oxime-induced hepatotoxicity in vitro

Horn, Gabriele; Kranawetvogl, Tamara; John, Harald; Weigel, Carlotta; Rauen, Ursula; Worek, Franz; Wille, Timo

doi:10.1016/j.cbi.2022.110285

Cited by 6 publications

(3 citation statements)

References 40 publications

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“…According to the U.S. medical management guidelines, British clinicians treating victims of A-234 poisoning noticed that high doses of pralidoxime helped maintain the blood pressure and renal perfusion and, therefore, may provide some benefit (U.S. Government 2019 ). On the other hand, oximes affect liver functions and may induce hepatotoxicity, especially at high doses (Pejchal et al 2008 ; Horn et al 2023 ). Indeed, Steindl et al treated an A-234 victim with obidoxime.…”

Section: Discussionmentioning

confidence: 99%

A-series agent A-234: initial in vitro and in vivo characterization

Hrabinova,

Pejchal,

Hepnarova

et al. 2024

Arch Toxicol

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A-series agent A-234 belongs to a new generation of nerve agents. The poisoning of a former Russian spy Sergei Skripal and his daughter in Salisbury, England, in March 2018 led to the inclusion of A-234 and other A-series agents into the Chemical Weapons Convention. Even though five years have already passed, there is still very little information on its chemical properties, biological activities, and treatment options with established antidotes. In this article, we first assessed A-234 stability in neutral pH for subsequent experiments. Then, we determined its inhibitory potential towards human recombinant acetylcholinesterase (HssAChE; EC 3.1.1.7) and butyrylcholinesterase (HssBChE; EC 3.1.1.8), the ability of HI-6, obidoxime, pralidoxime, methoxime, and trimedoxime to reactivate inhibited cholinesterases (ChEs), its toxicity in rats and therapeutic effects of different antidotal approaches. Finally, we utilized molecular dynamics to explain our findings. The results of spontaneous A-234 hydrolysis showed a slow process with a reaction rate displaying a triphasic course during the first 72 h (the residual concentration 86.2%). A-234 was found to be a potent inhibitor of both human ChEs (HssAChE IC50 = 0.101 ± 0.003 µM and HssBChE IC50 = 0.036 ± 0.002 µM), whereas the five marketed oximes have negligible reactivation ability toward A-234-inhibited HssAChE and HssBChE. The acute toxicity of A-234 is comparable to that of VX and in the context of therapy, atropine and diazepam effectively mitigate A-234 lethality. Even though oxime administration may induce minor improvements, selected oximes (HI-6 and methoxime) do not reactivate ChEs in vivo. Molecular dynamics implies that all marketed oximes are weak nucleophiles, which may explain the failure to reactivate the A-234 phosphorus-serine oxygen bond characterized by low partial charge, in particular, HI-6 and trimedoxime oxime oxygen may not be able to effectively approach the A-234 phosphorus, while pralidoxime displayed low interaction energy. This study is the first to provide essential experimental preclinical data on the A-234 compound.

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Section: Discussionmentioning

confidence: 99%

A-series agent A-234: initial in vitro and in vivo characterization

Hrabinova,

Pejchal,

Hepnarova

et al. 2024

Arch Toxicol

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“…147 Horn et al constructed HepaRG liver spheroids to study phridinium oxidme-induced hepatotoxicity, and they revealed the marginal cytotoxicity is at concentrations up to 2000 μM for the individual oximes pralidoxime, obidoxime, HI-6, and MMB-4 and the organophosphate malathion. 148 Renner et al generated standardized human automated midbrain organoids (AMOs) to screen a library of 84 compounds, demonstrating higher sensitivity in 3D AMOs than in 2D culture to the known neurotoxic effects of the pesticide lindane. 149 Metal ion is another risk factor in food safety issues.…”

Section: Ive Systems In Food Toxicology Analysismentioning

confidence: 99%

Exploitation of In Vivo-Emulated In Vitro System in Advanced Food Science

et al. 2023

J. Agric. Food Chem.

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Reasonable model construction contributes to the accuracy of experimental results. Multiple in vivo models offer reliable choices for effective evaluation, whereas their applications are hampered due to adverse features including high time-consumption, high cost and ethical contradictions. In vivo-emulated in vitro systems (IVE systems) have experienced rapid development and have been brought into food science for about two decades. IVE systems’ flexibly gathers the strengths of in vitro and in vivo models into one, reflecting the results in an efficient, systematic and interacted manner. In this review, we comprehensively reviewed the current research progress of IVE systems based on the literature published in the recent two decades. By categorizing the IVE systems into 2D coculture models, spheroids and organoids, their applications were systematically summarized and typically exemplified. The pros and cons of IVE systems were also thoroughly discussed, drawing attention to present challenges and inspiring potential orientation and future perspectives. The wide applicability and multiple possibilities suggest IVE systems as an effective and persuasive platform in the future of advanced food science.

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“…Nevertheless, British clinicians who treated the victims implied that high doses of pralidoxime helped stabilize cardiac parameters and renal function, possibly through non-targeted interactions with extrasynaptic cholinergic receptors (CHEMM 2019 ; Hatfill 2019 ). On the other hand, high oxime doses may impair liver functions (Marrs et al 2007 ; Pejchal et al 2008 ; Horn et al 2023 ). Steindl et al ( 2021 ) observed elevated transaminases and γ-glutamyl transferase several days after they stopped the oxime therapy.…”

Section: Introductionmentioning

confidence: 99%

A-agents, misleadingly known as “Novichoks”: a narrative review

Opravil,

Pejchal,

Finger

et al. 2023

Arch Toxicol

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Abstract“Novichok” refers to a new group of nerve agents called the A-series agents. Their existence came to light in 2018 after incidents in the UK and again in 2020 in Russia. They are unique organophosphorus-based compounds developed during the Cold War in a program called Foliant in the USSR. This review is based on original chemical entities from Mirzayanov's memoirs published in 2008. Due to classified research, a considerable debate arose about their structures, and hence, various structural moieties were speculated. For this reason, the scientific literature is highly incomplete and, in some cases, contradictory. This review critically assesses the information published to date on this class of compounds. The scope of this work is to summarize all the available and relevant information, including the physicochemical properties, chemical synthesis, mechanism of action, toxicity, pharmacokinetics, and medical countermeasures used to date. The environmental stability of A-series agents, the lack of environmentally safe decontamination, their high toxicity, and the scarcity of information on post-contamination treatment pose a challenge for managing possible incidents.

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Human HepaRG liver spheroids: cold storage protocol and study on pyridinium oxime-induced hepatotoxicity in vitro

Cited by 6 publications

References 40 publications

A-series agent A-234: initial in vitro and in vivo characterization

A-series agent A-234: initial in vitro and in vivo characterization

Exploitation of In Vivo-Emulated In Vitro System in Advanced Food Science

A-agents, misleadingly known as “Novichoks”: a narrative review

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