The influence of soman simulator on reactivation by HI-6 of soman-inhibited acetylcholinesterase in preparations of rat and human skeletal muscle.
The aim of our study was to elucidate the phenomenon called "soman depot". Our investigations were focused on the depot formed in the skeletal muscle and on the effects of 1,2,2-trimethylpropyl dimethylphosphonate (PDP), a reported blocker of soman depot formation. The following questions were addressed: (1) how much of acetylcholinesterase (EC 3.1.1.7, AChE) activity can additionally be recovered by Hagedorn bispiridinium oxime reactivator 2-hydroxyimino-methylpyridinium-1-methyl-4'-carbamoyl-pyridinium-1 '-methylether dichloride monohydrate (HI-6) in the skeletal muscle preparations if they are pretreated by PDP prior to incubation in soman (1,2,2-trimethylpropyl methylphosphonofluoridate)? (2) Is this effect uniform along the muscle fibre or different in the endplate in comparison to the endplate-free region? (3) Is the effect of PDP species specific, i.e. does it differ between rat and human muscle? (4) What are the molecular mechanisms of the effects of PDP? PDP pretreatment increased the reactivation of soman-inhibited AChE by HI-6 in both regions of rat skeletal muscle. This increase was smaller in human skeletal muscle. The PDP-mediated increase in HI-6 reactivation was most efficient in the endplate-rich region of rat diaphragm as demonstrated biochemically and histochemically, but it could not be explained by the blockade of soman depot alone since it was also observed at low soman concentrations, at which soman depot is not supposed to form. This PDP effect could be better explained by the direct interactions of PDP with AChE resulting in decreased AChE phosphorylation. Soman concentration-dependent increase in HI-6 reactivation by PDP, which was more efficient at a high than a low soman concentration and could therefore originate from blockade of soman depot, was observed in the endplate-free region of rat diaphragm. It was also found in human muscle but was again smaller in this species. According to our EPR study, solubilization of soman in the lipophilic cell membrane compartment can be excluded as a mechanism producing significant soman depot. In general, our results suggest a more complex mechanism of PDP action than reported previously.
Brank
M
M
Institute of Pathophysiology, School of Medicine, University of Ljubljana, Slovenia.
Sentjurc
M
M
Stalc
A
A
Grubic
Z
Z
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D002802:Cholinesterases / Q000378:metabolism; D003964:Diaphragm / Q000201:enzymology; D004578:Electron Spin Resonance Spectroscopy; D004593:Electrophorus; D006801:Humans; D066298:In Vitro Techniques; D008954:Models, Biological; D009045:Motor Endplate / Q000201:enzymology; D009132:Muscles / Q000187:drug effects / Q000201:enzymology*; D010091:Oximes; D010766:Phosphorylation; D011726:Pyridinium Compounds / Q000494:pharmacology*; D051381:Rats; D012999:Soman / Q000031:analogs & derivatives / Q000494:pharmacology*
D002801:Cholinesterase Reactivators; D010091:Oximes; D011726:Pyridinium Compounds; C048957:pinacolyl dimethylphosphinate; D012999:Soman; D002802:Cholinesterases; C022870:asoxime chloride; D000109:Acetylcholine