646 13. REVERSAL OF INHIBITION 



muscular, and glandular functional activity for long periods of time. Both 

 of these groups of inhibitors contain members that do not produce com- 

 pletely irreversible inactivation and with these the return to activity is 

 dependent on the rate of spontaneous enzyme reactivation as well as re- 

 synthesis of the enzyme. 



Effective reversal of intracellular inhibition by the addition of a sub- 

 stance binding the inhibitor is well documented and is the basis for the 

 clinical use of dimercaprol in heavy metal poisoning. Walker in 1928 

 showed that the ciliate Colpidium. immobilized by various arsenicals could 

 be rapidly restored by the addition of thioglycolate and in Voegtlin's 

 laboratory (Voegtlin et al., 1931) it was soon demonstrated that glutathione 

 would restore tissue respiration depressed by arsenicals. Since that time 

 many instances of such reversal by a variety of sulf hydryl compounds have 

 been reported, culminating in the discovery of the particular effectiveness 

 of dimercaprol. The injection of dimercaprol into an animal previously 

 treated with an arsenical produces a very rapid increase in the urinary 

 excretion of the arsenical (Eagle et al., 1946). This sudden burst of urinary 

 arsenical is accompanied by a rise in plasma arsenic and is due primarily 

 to the withdrawal of the arsenical from the tissues. The dimercaprol prob- 

 ably binds the free arsenical in both the blood and tissue cells since the 

 cells are permeable to this reversor, but it is not necessary for the reversor 

 to penetrate into the cells to reverse the inhibition. Danielli et al., (1947) 

 showed that dimercaprol glucoside (BAL-INTRAV), which presumably 

 enters cells with difficulty, is effective in combatting the toxic actions of 

 arsenicals. This would be expected inasmuch as there is an equilibrium 

 between free inhibitor in the plasma, in the extracellular fluid, in the cy- 

 toplasm, and bound arsenical. Reduction of the free arsenical in the plasma 

 to near zero would withdraw arsenical from the tissues at the same rate 

 as would be observed if the tissue were placed in an inhibitor-free medium. 



Kinetics of Organophosphorus Poisoning and Its Treatment 



The time course of the poisoning resulting from the administration of 

 organophosphorus inhibitors to animals is probably quite complex because 

 of the numerous reactions occurring. A very interesting mathematical treat- 

 ment of such poisoning was developed by Green (1958) and this can be ap- 

 plied, to varying extents, to other inhibitions or poisonings by irreversible 

 inhibitors. It was assumed that the inhibitor can undergo the following 

 reactions: (1) combination with enzymes, (2) spontaneous inactivation, (3) 

 inactivation by substances present in the body, and (4) reactivation of the 

 inhibited enzyme. The approach used by Green is different from that pre- 

 sented previously in the chapter because his object was to determine the 

 dosages of the inhibitors necessary to produce a lethal level of enzyme 

 inhibition. His treatment will be described for two common situations. 



