Effect of different oximes on rat and human cholinesterases inhibited by methamidophos: a comparative in vitro and in silico study.
Methamidophos is one of the most toxic organophosphorus (OP) compounds. It acts via phosphorylation of a serine residue in the active site of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), leading to enzyme inactivation. Different oximes have been developed to reverse this inhibition. Thus, our work aimed to test the protective or reactivation capability of pralidoxime and obidoxime, as well as two new oximes synthesised in our laboratory, on human and rat cholinesterases inhibited by methamidophos. In addition, we performed molecular docking studies in non-aged methamidophos-inhibited AChE to understand the mechanisms involved. Our results suggested that pralidoxime protected and reactivated methamidophos-inhibited rat brain AChE. Regarding human erythrocyte AChE, all oximes tested protected and reactivated the enzyme, with the best reactivation index observed at the concentration of 50 μM. Concerning BChE, butane-2,3-dionethiosemicarbazone oxime (oxime 1) was able to protect and reactivate the methamidophos-inhibited BChE by 45% at 50 μM, whereas 2(3-(phenylhydrazono)butan-2-one oxime (oxime 2) reactivated 28% of BChE activity at 100 μM. The two classical oximes failed to reactivate BChE. The molecular docking study demonstrated that pralidoxime appears to be better positioned in the active site to attack the O-P moiety of the inhibited enzyme, being near the oxyanion hole, whereas our new oximes were stably positioned in the active site in a manner similar to that of obidoxime. In conclusion, our work demonstrated that the newly synthesised oximes were able to reactivate not only human erythrocyte AChE but also human plasma BChE, which could represent an advantage in the treatment of OP compounds poisoning.
Department of Chemistry, Federal University of Santa Maria, Santa Maria, Rio Grande do Sul, Brazil.
Thiago Henrique
TH
Lugokenski
Priscila
P
Gubert
Diones Caeran
DC
Bueno
Pablo Andrei
PA
Nogara
Rogério
R
de Aquino Saraiva
Rômulo Pillon
RP
Barcelos
Vanessa Santana
VS
Carratu
Leandro
L
Bresolin
Nilda Berenice
NB
de Vargas Barbosa
Maria Ester
ME
Pereira
João Batista Teixeira
JB
da Rocha
Félix Alexandre Antunes
FA
Soares
D000110:Acetylcholinesterase / Q000097:blood; D000818:Animals; D002091:Butyrylcholinesterase / Q000097:blood; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007306:Insecticides / Q000633:toxicity*; D008297:Male; D009768:Obidoxime Chloride / Q000494:pharmacology*; D009946:Organothiophosphorus Compounds / Q000633:toxicity*; D011220:Pralidoxime Compounds / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D007306:Insecticides; D009946:Organothiophosphorus Compounds; D011220:Pralidoxime Compounds; D009768:Obidoxime Chloride; C014655:methamidophos; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; C028797:pralidoxime