engleski

Assessment of hepatoprotective effects K048 oxime in tabun-poisoned rats: the alkaline comet assay study

Aim: Oximes play an important role in the elimination of toxic effects caused by chemical warfare agents, especially in the cases resistant to the atropine treatment alone. K048 oxime as one of the promising antidote in humans recently showed an acceptable genotoxic profile. Present study is focused on potential hepatoprotective effects of K048 effects in vivo. Methods: We selected a model of tabun- poisoned rats, which were given K048 oxime to relieve symptoms of tabun-poisoning. The levels of primary DNA damage in liver cells were studied using the alkaline comet assay 1, 6 and 24 h after the treatments. Sixty male adult Wistar rats were divided in five groups according to the treatment: (1) tabun-poisoned (75% LD50, s.c.), (2) K048-treated (25% LD50 i.p.), (3) atropine-treated (10 mg kg-1, i.p.) after tabun poisoning (75% LD50, s.c.), (4) concomitant treatment with K048 (25% LD50, i.p.) and atropine (10 mg kg-1, i.p.) after tabun poisoning (75% LD50, s.c.), and (5) negative controls given saline only (2 mL kg-1, i.p.). Results: Tabun itself caused the highest level of primary DNA damage in hepatocytes 24 h after its administration. K048 oxime had an acceptable genotoxicity profile at each time point. Its hepatoprotective effects were obvious at each time point studied, and in all cases the levels of primary DNA damage measured in oxime-treated groups were lower or similar as compared to negative control. Minor differences in the genotoxicity observed between the time-points studied could be explained by the metabolism of the compound. Concomitant administration of K048 with atropine changed its genotoxicity profile in the hepatocytes, especially 6 h after treatment. Conclusions: K048 effectively counteracted the poisoning of rats by tabun, both alone and in combination with atropine. Hepatoprotective effects speak in favour of K048 as a promising molecule for therapeutic treatment against fatal poisoning with chemical warfare agents.

Oximes; organophosphorus poisoning; tabun; DNA damage; genotoxicity

nije evidentirano