title: In vitro reactivating effects of standard and newly developed oximes on malaoxon-inhibited mouse brain acetylcholinesterase.
abstract: Malathion is an organophosphate (OP) pesticide whose toxicity depends on its bioactivation to malaoxon. Human malathion poisoning has been treated with oximes (mainly pralidoxime) in an attempt to reactivate OP-inhibited acetylcholinesterase (AChE). However, pralidoxime has shown unsatisfactory therapeutic effects in malathion poisoning and its routine use has been questioned. In this study, we evaluated the in vitro potency of standards and newly developed oximes in reactivating malaoxon-inhibited AChE derived from mouse brain supernatants. Malaoxon displayed a concentration-dependent inhibitory effect on mouse brain AChE (IC(50) = 2.36 microM), and pralidoxime caused a modest reactivating effect (30% of reactivation at 600 microM). Obidoxime and trimedoxime, as well as K047 and K075, displayed higher reactivating effects (from 55% to 70% of reactivation at 600 muM) when compared with pralidoxime. The results show that obidoxime, trimedoxime, K074 and K075 present higher reactivating effects on malaoxon-inhibited AChE under in vitro conditions when compared with pralidoxime. Taking into account the unsatisfactory effects of pralidoxime as antidotal treatment in malathion poisonings, the present results suggest that obidoxime, trimedoxime, K074 and K075 might be interesting therapeutic strategies to reactivate malaoxon-inhibited AChE in malathion poisonings.
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil.
authors.forename: Alessandra Antunes
authors.initials: AA
authors.lastname: dos Santos
authors.forename: Danúbia Bonfanti
authors.initials: DB
authors.lastname: dos Santos
authors.forename: Alcir Luiz
authors.initials: AL
authors.lastname: Dafre
authors.forename: Andreza Fabro
authors.initials: AF
authors.lastname: de Bem
authors.forename: Diogo Onofre
authors.initials: DO
authors.lastname: Souza
authors.forename: João Batista Teixeira
authors.initials: JB
authors.lastname: da Rocha
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuca
authors.forename: Marcelo
authors.initials: M
authors.lastname: Farina
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002073:Butanes / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D004794:Enzyme Repression / Q000187:drug effects; D007306:Insecticides / Q000633:toxicity*; D008294:Malathion / Q000031:analogs & derivatives* / Q000633:toxicity; D008297:Male; D051379:Mice; D009768:Obidoxime Chloride / Q000494:pharmacology; D010091:Oximes / Q000494:pharmacology*; D011220:Pralidoxime Compounds / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000494:pharmacology; D014289:Trimedoxime / Q000494:pharmacology
chemical_list: C515196:1,4-bis(4-hydroxyiminomethylpyridinium)butane dibromide; C481758:1-(4-hydroxyiminomethylpyridinium)-3-(carbamoylpyridinium) propane dibromide; C488676:1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium)butane; D000931:Antidotes; D002073:Butanes; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D007306:Insecticides; C518856:K075 compound; D010091:Oximes; D011220:Pralidoxime Compounds; D011726:Pyridinium Compounds; C100082:malaoxon; D009768:Obidoxime Chloride; D014289:Trimedoxime; C005514:N,N'-monomethylenebis(pyridiniumaldoxime); D000110:Acetylcholinesterase; C028797:pralidoxime; D008294:Malathion