Acute tabun toxicity; biochemical and histochemical consequences in brain and skeletal muscles of rat.
Male Sprague-Dawley rats injected s.c. with an acute non-lethal dose (200 micrograms/kg) of ethyl N,N-dimethylphosphoramidocyanidate (tabun) showed onset of hypercholinergic activity within 10-15 min. The maximal severity of toxicity signs was evident within 0.5-1 h and persisted for 6 h. Except for mild tremors no overt toxicity signs were evident after 24 h. Within 1 h a dramatic decline of acetylcholinesterase (AChE) activity occurred in all the brain structures (less than 3%) and skeletal muscles (less than 10% in soleus and hemi-diaphragm; and 32% in extensor digitorum longus (EDL)). No significant recovery was seen up to 48-72 h. Within 7 days rats became free of toxicity signs and AChE activity had recovered to about 40% in brain structures (except cortex, 14%) and 65-70% in skeletal muscles. Within 1 h the 16 S molecular form of AChE located at the neuromuscular junction was most severely inhibited in soleus, followed by hemi-diaphragm and least in the EDL, and had fully recovered in all the muscles when examined after day 7. Muscle fiber necrosis developed within 1-3 h in soleus and hemi-diaphragm and after a delay of 24 h in EDL. The highest number of necrotic lesions in all muscles was seen at 72 h with the hemi-diaphragm maximally affected and EDL the least. To determine detoxification of tabun by non-specific binding, the activity of butyrylcholinesterase (BuChE) and carboxylesterase (CarbE) was measured. The inhibition and recovery pattern of BuChE activity was quite similar to that of AChE, except that the rate of recovery was more rapid. Within 1 h the remaining activity of CarbE was 10% in plasma, about 30% in brain structures, and 79% in liver; recovery was complete within 7 days. The inhibition of BuChE and CarbE can serve as a protective mechanism against tabun toxicity by reducing the amount available for AChE inhibition. The prolonged AChE inhibition in muscle and brain may indicate storage of tabun and delayed release from non-enzymic sites. Since tabun is a cyanophosphorus compound, the toxic effects from the released cyanide (CN) could be another reason for the delayed recovery after tabun.
Gupta
R C
RC
Department of Pharmacology, School of Medicine, Vanderbilt University, Nashville, TN 37232.
Patterson
G T
GT
Dettbarn
W D
WD
D000110:Acetylcholinesterase / Q000032:analysis; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002091:Butyrylcholinesterase / Q000032:analysis; D043182:Carboxylesterase; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D006651:Histocytochemistry; D008297:Male; D009132:Muscles / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009336:Necrosis; D010755:Organophosphates / Q000633:toxicity*; D009943:Organophosphorus Compounds / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
D002800:Cholinesterase Inhibitors; D010755:Organophosphates; D009943:Organophosphorus Compounds; D002265:Carboxylic Ester Hydrolases; D043182:Carboxylesterase; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; C009374:tabun