In vitro evaluation of HI-6 oxime: mode of interaction with AChE inhibited by irinotecan and its cytotoxicity

The function of acetylcholinesterase (AChE) is the rapid hydrolysis of the neurotransmitter acetylcholine (ACh), which is involved in the numerous cholinergic pathways in both, the central and the peripheral nervous system. Therefore, AChE measurement is of high value for therapy management, especially during the course of the intoxication with different chemicals or drugs that inhibits activity of enzyme. For the recovery of inhibited enzyme, derivatives from the group of pyridinium or bispyridinium aldoximes (oximes) are used. Adverse effects of these substances are not well elucidated, because of their narrow and one-shot usage. In this study we evaluated the in vitro efficacy of oxime HI-6 to protect and/or reactivate human erythrocyte AChE inhibited by anticancer drug irinotecan, which cause acute cholinergic syndrome after its administration. Moreover, using alkaline comet assay possible genotoxic effects of HI-6 were evaluated on human peripheral blood leukocytes. HI-6 increases the activity of AChE to 30% ; residual activity after irinotecan inhibition was 7%. Also, it reactivated the enzyme by 40% when applied in a concentration of ¼ of the IC50 value. None of the tested concentrations of HI-6 was genotoxic as estimated by evaluation of three main comet parameters: tail length, tail intensity and tail moment. The results obtained sustain the further investigation of HI-6 in vivo, as well as its development for possible application in chemotherapy.