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Effects of 1,1′-oxydimethylene bis-(4-tert-butylpyridinium chloride) (SAD-128) and decamethonium on reactivation of soman- and sarin-inhibited cholinesterase by oximes

1978; Elsevier BV; Volume: 27; Issue: 5 Linguagem: Inglês

10.1016/0006-2952(78)90516-6

1873-2968

Larrel W. Harris, William C. Heyl, David L. Stitcher, Clarence A. Broomfield,

Environmental Toxicology and Ecotoxicology

The effects of 1,1′-oxydimethylene bis-(4-tert-butylpyridinium chloride) (SAD-128) and decamethonium on reactivation by oxime of Soman- and Sarin-inhibited erythrocyte acetylcholinesterase (AChE; EC 3.1.1.7) are reported. The inclusion of SAD-128 or decamethonium (10−3 M) together with either TMB-4 or Toxogonin markedly augmented the reactivation of Soman- or Sarin-inhibited AChE; the recovery of enzyme activity was more than doubled in each instance when compared to the recovery in the presence of oxime alone. No reactivation was observed with SAD-128 or decamethonium in the absence of oxime. The i.v. ld50 of SAD-128 in rabbits is 11.9 mg/kg. When 5 mg/kg of SAD-128 was given i.v. to rabbits 2 min before poisoning with Soman. 15–20 per cent of the blood cholinesterase was protected from inhibition by Soman. The aging rate in vitro of Soman-inhibited erythrocyte AChE was decreased by a factor of 1.9 with 10−3 M SAD-128. A concentration of 1.4 × 10−4M SAD-128 reduced the rate of acetylcholine hydrolysis by erythrocyte AChE in vitro to 50 per cent of control. We suggest that SAD-128 protects against inhibition by Soman due to its ability to function as a reversible inhibitor and that SAD-128 and decamethonium might be allosteric modifiers of the inhibited enzyme, rendering it more susceptible to reactivation by TMB-4 or Toxogonin.