engleski

Dose and time-dependent effects of imidazolium oximes on human kidney cells

Constant improvements to the drug selection process are crucial to select only the best candidates for further in vivo research, minimize the sacrifice of laboratory animals and reduce costs. Such improvements include cell-based in vitro toxicology as the leading branch of laboratory research. In the search for new antidotes for organophosphorus compound poisoning, we implemented this approach and evaluated a structurally cognate series of promising imidazolium antidotes to elucidate which of them are to be pointed out as leads for future studies. The cytotoxic effect was tested on two human kidney cell lines treated with a wide oxime concentration range through a minimum of three time points (1, 4 and 24 h). The results were compared to the medically approved antidote HI-6. As the results indicated, the time-dependent toxicity of the tested oximes was related to their structure, and the ones having an additional phenyl ring with an attached chlorine or methyl moiety were the most toxic to the tested cells. The IC50 values were in μM range. Toxicity was additionally confirmed by measuring LDH activity and it indicated unregulated cell death necrosis. The detailed mechanisms responsible for toxicity need to be further determined and our results indicated that the tested imidazolium antidotes are troublesome when considered as candidates for further antidote development. Acknowledgment: This work was supported in part by the Croatian Science Foundation under the project UIP-2017-05-7260.

oximes ; cytotoxicity ; time-dependent ; kidney cells ; LDH

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