Synthesis of cholinesterase following poisoning with irreversible anticholinesterases: Effects of theophylline and N 6,O 2-dibutyryl adenosine 3′,5′-monophosphate on synthesis and survival

Abstract

The half-time ( t 1 2 ) for return of whole blood cholinesterase (ChE) activity in mice following poisoning with Soman and DFP is on the order of 30 hr; in rats, the t 1 2 for return of whole blood ChE is 32 hr for Soman and 106 hr for DFP. In fact, the recovery of ChE activity in other rat tissues (liver and brain) is also significantly ( p < 0.001) slower after DFP poisoning than after Soman poisoning. It appears that DFP adversely affects the normal rate for synthesis of ChE in rats; DFP does not affect overall protein synthesis in the rat as measured by 14C-amino acid incorporation into protein. Pretreatment of mice with a combination of theophylline-DBcAMP before poisoning with Soman causes animals to be more sensitive to the poison. Treatment of mice and rats with theophylline-DBcAMP at 24, 29, and 45 hr after Soman poisoning produces a dramatic increase in whole blood ChE but not in brain ChE at 48 hr; this increase in enzyme activity is due to pseudo-ChE and not acetyl-ChE. Ethionine, injected 1 hr before the initial dose of theophylline-DBcAMP, completely abolished the enhanced ChE activity observed in whole blood. These results suggest that the enhanced ChE activity observed in blood is due to a stimulating effect of the drugs on de novo synthesis and/or a release of ChE by the liver.