title: The cholinergic and non-cholinergic effects of organophosphates and oximes in cultured human myoblasts.
abstract: Organophosphorus compounds (OPs) and oximes may interfere with other molecules than AChE in the living systems, affecting in this way various cellular processes and underlying mechanisms. These non-cholinergic effects may contribute to the clinical status in OP poisoning and therefore deserve equal scientific attention. Here, we investigated the effects of tabun and oxime K048 on the processes known to be involved in muscle response to the environmental factors, like IL-6 release and the regulation of the heat shock proteins (HSPs). While IL-6 stimulates muscle regeneration, which follows well known OP-induced myopathy, HSPs have cytoprotective effect against various stress factors including xenobiotics. All our experiments were carried out on cultured human myoblasts, as the precursors of muscle regeneration. We found unchanged AChE mRNA level after tabun/K048 treatment meaning that tabun and K048 did not interfere with the transcription or stability of this mRNA in the time period tested, even if AChE catalytic activity was significantly affected. On the other hand, after myoblast exposure to tabun, we observed significant changes in the protein levels of HSP 27 and in the secretion of IL-6. Namely, secretion of IL-6 decreased to 53% and the level of HSP 27 increased by 34% compared to the control level. Both effects were attenuated if myoblasts were pretreated with oxime K048, but not if they were treated with K048 after exposure to tabun. The molecular mechanism underlying these effects remains to be elucidated. However, it seems that these effects could be associated with OPs and oximes as a specific group of compounds rather than as a specific compound itself. Overall, the effects of OPs and oximes demonstrated here might play an important role in muscle regeneration which importantly determines the final outcome of OP myotoxicity.
authors.affiliation: Institute for Medical Research and Occupational Health, Zagreb, Croatia.
authors.forename: Maja
authors.initials: M
authors.lastname: Katalinić
authors.forename: Katarina
authors.initials: K
authors.lastname: Miš
authors.forename: Sergej
authors.initials: S
authors.lastname: Pirkmajer
authors.forename: Zoran
authors.initials: Z
authors.lastname: Grubič
authors.forename: Zrinka
authors.initials: Z
authors.lastname: Kovarik
authors.forename: Tomaž
authors.initials: T
authors.lastname: Marš
mesh_terms: D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000494:pharmacology; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D018832:Molecular Chaperones; D032448:Myoblasts, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D010755:Organophosphates / Q000633:toxicity*; D010091:Oximes / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000494:pharmacology; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects / Q000235:genetics / Q000502:physiology
chemical_list: C488676:1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium)butane; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D058851:GPI-Linked Proteins; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; C508600:IL6 protein, human; D015850:Interleukin-6; D018832:Molecular Chaperones; D010755:Organophosphates; D010091:Oximes; D011726:Pyridinium Compounds; D012333:RNA, Messenger; C548244:ACHE protein, human; D000110:Acetylcholinesterase; C009374:tabun