engleski

The assessment of genotoxicity of a newly synthesized atropine-4-oxime on human lymphocytes in vitro

Present study aimed at the evaluation of genotoxicity of a newly synthesized substance with intriguing molecular structure in which an atropine part is coupled with oxime. Both atropine and oxime have important role in the management of acute cholinergic syndrome and are involved in the recovery of inhibited enzyme acetylcholinesterase (AChE). Preliminary studies on mice indicated that LD50 of the substance equals to 10 mg/kg. Here we evaluated the effects of doses that correspond to 5%LD50 and 1/4LD50. Study was performed on isolated human peripheral lymphocytes that were incubated in vitro for 30 min in the presence of test substance with and without metabolic activation. Lymphocyte viability, apoptosis/necrosis measurements, alkaline and neutral comet assay were performed immediately after the treatment. The results show that tested substance did not significantly impair the viability of lymphocytes. Metabolic activation slightly contributed to its toxicity only when administered at concentration of 5% LD50 and it was noticed as a non-significant increase of apoptotic cells. On the contrary, oxime applied in higher dose with metabolic activation significantly increased cell viability and decreased the incidence of necrotic cells. In the alkaline comet assay both tested concentrations evoked an increase in the tail intensity compared to negative control, but differences between samples with and without metabolic activation were not statistically significant. The results of neutral comet assay show that treatment with oxime in both tested concentrations did not significantly influence integrity of lymphocyte DNA. Taken together, the findings of this study indicate an acceptable genotoxic profile of atropine-oxime on human lymphocytes in vitro, but its activity should be further tested on other cell types and animal model to elucidate whether it is a source molecule promising for application in vivo as an efficient antidote in organophosphorus poisoning.

atropine-4-oxime; genotoxicity; human lymphocytes

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