Poisoning with organophosphorus compounds used as pesticides or misused as chemical weapons remains a serious threat to human health and life. Their toxic effects result from irreversible blockade of the enzymes acetylcholinesterase and butyrylcholinesterase, which causes overstimulation of the cholinergic system and often leads to serious injury or death. Treatment of organophosphorus poisoning involves, among other strategies, the administration of oxime compounds. Oximes reactivate cholinesterases by breaking the covalent bond between the serine residue from the enzyme active site and the phosphorus atom of the organophosphorus compound. Although the general mechanism of reactivation has been known for years, the exact molecular aspects determining the efficiency and selectivity of individual oximes are still not clear. This hinders the development of new active compounds. In our research, using relatively simple and widely available molecular docking methods, we investigated the reactivation of acetyl- and butyrylcholinesterase blocked by sarin and tabun. For the selected oximes, their binding modes at each step of the reactivation process were identified. Amino acids essential for effective reactivation and those responsible for the selectivity of individual oximes against inhibited acetyl- and butyrylcholinesterase were identified. This research broadens the knowledge about cholinesterase reactivation and demonstrates the usefulness of molecular docking in the study of this process. The presented observations and methods can be used in the future to support the search for new effective reactivators.

• Klíčová slova
• acetylcholinesterase, butyrylcholinesterase, docking studies, molecular modeling, organophosphates, reactivation process, reactivators,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• aktivace enzymů MeSH
• butyrylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory farmakologie   MeSH
• fosfor chemie   MeSH
• katalytická doména MeSH
• konformace proteinů MeSH
• kvantová teorie MeSH
• lidé MeSH
• ligandy MeSH
• molekulární modely MeSH
• myši MeSH
• organofosfáty chemie   MeSH
• oximy chemie   MeSH
• proteosyntéza MeSH
• reaktivátory cholinesterasy farmakologie   MeSH
• sarin chemie   MeSH
• shluková analýza MeSH
• simulace molekulového dockingu * MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• fosfor MeSH
• ligandy MeSH
• organofosfáty MeSH
• oximy MeSH
• reaktivátory cholinesterasy MeSH
• sarin MeSH
• tabun MeSH Prohlížeč

The detrimental effects of organophosphates (OPs) on human health are thought to be of systemic, i.e., irreversible inhibition of acetylcholinesterase (AChE) at nerve synapses. However, several studies have shown that AChE inhibition alone cannot explain all the toxicological manifestations in prolonged exposure to OPs. The present study aimed to assess the status of antioxidants malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) (reduced), catalase, and ferric reducing antioxidant power (FRAP) in chronic OP-exposed groups from Cameroon and Pakistan. Molecular analysis of genetic polymorphisms (SNPs) of glutathione transferases (GSTM1, GSTP1, GSTT1), catalase gene (CAT, rs7943316), sirtuin 1 gene (SIRT1, rs10823108), acetylcholinesterase gene (ACHE, rs2571598), and butyrylcholinesterase gene (BCHE, rs3495) were screened in the OP-exposed individuals to find the possible causative association with oxidative stress and toxicity. Cholinesterase and antioxidant activities were measured by colorimetric methods using a spectrophotometer. Salting-out method was employed for DNA extraction from blood followed by restriction fragment length polymorphism (RFLP) for molecular analysis. Cholinergic enzymes were significantly decreased in OP-exposed groups. Catalase and SOD were decreased and MDA and FRAP were increased in OP-exposed groups compared to unexposed groups in both groups. GSH was decreased only in Pakistani OPs-exposed group. Molecular analysis of ACHE, BCHE, Catalase, GSTP1, and GSTM1 SNPs revealed a tentative association with their phenotypic expression that is level of antioxidant and cholinergic enzymes. The study concludes that chronic OPs exposure induces oxidative stress which is associated with the related SNP polymorphism. The toxicogenetics of understudied SNPs were examined for the first time to our understanding. The findings may lead to a newer area of investigation on OPs induced health issues and toxicogenetics.

• Klíčová slova
• SNPs, antioxidants, cholinergic enzymes, organophosphates, toxicogenetics,
• MeSH
• acetylcholinesterasa genetika   MeSH
• butyrylcholinesterasa genetika   MeSH
• dospělí MeSH
• glutathion-S-transferasa fí genetika   MeSH
• glutathion MeSH
• glutathiontransferasa genetika   MeSH
• GPI-vázané proteiny genetika   MeSH
• interakce genů a prostředí * MeSH
• jednonukleotidový polymorfismus * MeSH
• katalasa genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• malondialdehyd MeSH
• mladiství MeSH
• mladý dospělý MeSH
• organofosforové sloučeniny škodlivé účinky   MeSH
• oxidační stres genetika   MeSH
• sirtuin 1 genetika   MeSH
• vystavení vlivu životního prostředí škodlivé účinky   analýza   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Kamerun MeSH
• Pákistán MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• ACHE protein, human MeSH Prohlížeč
• BCHE protein, human MeSH Prohlížeč
• butyrylcholinesterasa MeSH
• glutathion-S-transferasa fí MeSH
• glutathion MeSH
• glutathione S-transferase M1 MeSH Prohlížeč
• glutathione S-transferase T1 MeSH Prohlížeč
• glutathiontransferasa MeSH
• GPI-vázané proteiny MeSH
• GSTP1 protein, human MeSH Prohlížeč
• katalasa MeSH
• malondialdehyd MeSH
• organofosforové sloučeniny MeSH
• SIRT1 protein, human MeSH Prohlížeč
• sirtuin 1 MeSH