In Vitro Evaluation of Oxidative Stress Induced by Oxime Reactivators of Acetylcholinesterase in HepG2 Cells

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60162694%3AG44__%2F24%3A00563134" target="_blank" >RIV/60162694:G44__/24:00563134 - isvavai.cz</a>

Alternative codes found

RIV/00216208:11160/23:10472801

Result on the web

<a href="https://pubs.acs.org/doi/epdf/10.1021/acs.chemrestox.3c00203" target="_blank" >https://pubs.acs.org/doi/epdf/10.1021/acs.chemrestox.3c00203</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.chemrestox.3c00203" target="_blank" >10.1021/acs.chemrestox.3c00203</a>

Result language

angličtina

Original language name

In Vitro Evaluation of Oxidative Stress Induced by Oxime Reactivators of Acetylcholinesterase in HepG2 Cells

Original language description

Oxime reactivators of acetylcholinesterase (AChE) are used as causal antidotes for intended and unintended poisoning by organophosphate nerve agents and pesticides. Despite all efforts to develop new AChE reactivators, none of these drug candidates replaced conventional clinically used oximes. In addition to the therapeutic efficacy, determining the safety profile is crucial in preclinical drug evaluation. The exact mechanism of oxime toxicity and the structure-toxicity relationship are subjects of ongoing research, with oxidative stress proposed as a possible mechanism. In the present study, we investigated four promising bispyridinium oxime AChE reactivators, K048, K074, K075, and K203, and their ability to induce oxidative stress in vitro. Cultured human hepatoma cells were exposed to oximes at concentrations corresponding to their IC50 values determined by the MTT assay after 24 h. Their potency to generate reactive oxygen species, interfere with the thiol antioxidant system, and induce lipid peroxidation was evaluated at 1, 4, and 24 h of exposure. Reactivators without a double bond in the four-carbon linker, K048 and K074, showed a greater potential to induce oxidative stress compared with K075 and K203, which contain a double bond. Unlike oximes with a three-carbon-long linker, the number of aldoxime groups attached to the pyridinium moieties does not determine the oxidative stress induction for K048, K074, K075, and K203 oximes. In conclusion, our results emphasize that the structure of oximes plays a critical role in inducing oxidative stress, and this relationship does not correlate with their cytotoxicity expressed as the IC50 value. However, it is important to note that oxidative stress cannot be disregarded as a potential contributor to the side effects associated with oximes.

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30107 - Medicinal chemistry

Project

<a href="/en/project/EF15_003%2F0000465" target="_blank" >EF15_003/0000465: Establishment of Specialized Team for Advanced Research on Separation Science</a><br>

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2023

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Chemical Research in Toxicology

ISSN

0893-228X

e-ISSN

1520-5010

Volume of the periodical

36

Issue of the periodical within the volume

12

Country of publishing house

US - UNITED STATES

Number of pages

9

Pages from-to

1912-1920

UT code for WoS article

001141620100001

EID of the result in the Scopus database

2-s2.0-85178130789