engleski

Potent lipophilic reactivators of phosphorylated cholinesterases are not cytotoxic and are metabolically stable

Organophosphate compounds (OPs) are still a plausible tool in wars and terroristic attacks where they are used as nerve agents (e.g. sarin, cyclosarin, VX, tabun). In addition, OP pesticides (e.g. paraoxon) cause more than a million acute poisonings per year worldwide. Their toxic mechanism is the inhibition of acetylcholinesterase (AChE) enzyme followed by the accumulation of acetylcholine in the synapses and cholinergic crisis. This can lead to respiratory arrest and death, whereas survivors experience long-term neurological impairments. Reactivation of OP-inhibited AChE is one of the approaches in therapy, but standard oxime reactivators (2-PAM, HI-6, obidoxime) are not potent enough for every OP and achieve low brain concentrations due to a permanent charge (quaternary nitrogen). Representatives of 3-hydroxy-2-pyridine aldoxime compounds, devoid of a permanent charge, were proven to be potent reactivators of AChE inhibited by VX, sarin, cyclosarin, tabun and paraoxon, and also showed the potency to efficiently detoxify OPs in whole human blood. Their blood-brain barrier penetration was predicted based on their physicochemical properties and in vitro PAMPA assay. In addition, logD7.4 values determined by chromatography confirmed their relatively high lipophilicity. To test whether the lipophilic character predisposes these oximes to exert toxic effects in the cells or be metabolized via the cytochrome P450 system, we used a cytotoxicity test in different cell lines and an incubation test with liver microsomes, respectively. The oximes were proven not to be toxic at physiologically relevant concentrations and to be metabolically stable. Supported by Croatian Science Foundation project (4307 ; 7260) and COGITO (2015−2016) (33068WE).

organophosphate poisoning ; uncharged lipophilic oximes, centrally active reactivators

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