686 6. ARSENICALS 



to reserve judgment. There is no doubt that thiamine deficiency and arsen- 

 ical poisoning cause similar metabolic and pathological changes, and quite 

 possibly for this reason the deficiency would make tissues more susceptible 

 to arsenicals, but one can argue that in the deficient tissue a smaller fraction 

 of the respiration would involve the keto acid oxidases and hence that arsen- 

 ical inhibition might be less than in normal tissue. 



The experimental temperature is an important factor in determining the 

 extent of respiratory inhibition by the arsenicals if the results obtained 

 by Myers et al. (1962) are generally applicable. The arsenite concentration 

 for 50% inhibition of rat thymocyte respiration is 1.8 mM at 25^ but only 

 0.15 mM at 37o, a 12-fold difference in potency. It is unlikely that this is 

 due to a more rapid reaction of the arsenite with the cell enzymes because 

 the oxygen uptake was measured over a period of 1-2 hr. Some workers 

 would conclude that this is another example in which the inhibition is corre- 

 lated with the respiratory rate. Others would interpret the results as a 

 shift in limiting reactions brought about by the temperature change. The 

 complex effects of temperature on cellular inhibitions in general and respir- 

 atory inhibitions in particular have been discussed (Chapter 1-15). 



Microorganisms are often able to develop resistance to the arsenicals 

 and it would be important to know if this is dependent on metabolic adapta- 

 tions. Trypanosomes resistant to oxophenarsine exhibit no obvious meta- 

 bolic differences with respect to substrate utilization, level of respiration, 

 or inhibition by a variety of substances, but it requires about 10 times the 

 concentration of oxophenarsine, relative to the normal strain, to depress 

 the respiration 50% (Harvey, 1949). If this resistance in the trypanosomes 

 is a matter of reduced permeability to the arsenical, for which there is 

 good evidence (page 766), this is a good example of how respiratory inhibi- 

 tion can be modified, not through change in the metabolic pattern but simply 

 by change in the degree to which the inhibitor can reach its site of action. 

 This could easily be checked by determining whether there is alteration 

 of the respiratory response to other arsenicals, such as arsenite, since the 

 permeability changes are reasonably specific. Mycobacteria resistant to 

 isoniazid do not show a modified respiratory response to arsenite (Miiller 

 etal, 1960). 



Inhibition of Tissue Respiration in Vivo 



In order to determine if respiratory inhibition occurs in the tissues 

 following the administration of arsenicals to animals, Elliott and Norris 

 (1945) injected rats intraperitoneally or subcutaneously with 25 mg/kg 

 AsgOg (which is lethal in 15 min and 50 min, respectively) and sacrificed 

 the animals when signs of imminent death occurred. The tissues were 

 removed, sliced, and their respiration measured (see accompanying tabu- 

 lation). The brain is quite resistant to respiratory depression, perhaps due 

 to the slow penetration of the arsenite into this tissue, but the question arises 



