VARIOUS METABOLIC PATHWAYS 693 



to urea. Cutler (1931 ) obtained similar results on dogs administered 75 mg/kg 

 arsphenamine intravenously (see accompanying tabulation), the blood 

 being obtained 25 hr later when the dogs were definitely toxic. Some of 



Concentration in blood (mg%) 



these changes are probably nonspecific in that they would occur during 

 various types of poisoning. The elevation in the guanidine level may be 

 the result of liver injury rather than of specific arsenical action. Since the 

 amino acids and proteins are often in dynamic equilibria, their levels depend- 

 ent on the rates of formation and utilization, a negative nitrogen balance 

 might indicate either an inhibition of synthesis or a stimulation of break- 

 down. 



Arsenicals should depress protein synthesis through interference with 

 the availability of certain amino acids, by depletion of ATP, and possibly 

 by direct actions on the synthetic pathway. The results in Table 6-8 make 

 clear the great variation in the sensitivities in different systems. One reason 

 for this is the different supplements used in noncellular preparations; 

 e. g., whether the ATP is provided or must be generated by oxidative phos- 

 phorylation; in the system studied by Weissbach (1960), the incorporation 

 of leucine was determined in a mixture of a particulate fraction, a soluble 

 fraction, RNA, Mg++, phosphate, ATP, and a thiol. Another possible reason 

 is that the whole sequence of protein synthesis was not measured in every 

 investigation, since amino acids can presumably be incorporated into non- 

 protein fractions. It is somewhat surprising, nevertheless, that arsenite is 

 so little inhibitory in some cases. Christiansen and Thimann (1950 c) found 

 that amino acids disappear during incubation of pea stem sections, and that 

 0.1 mM arsenite depresses the utilization of the amino acids 62%, while 

 inhibiting the formation of cell wall protein 11% and of plasma protein 

 71%. It is not known if arsenicals can exert a primary inhibition of protein 

 synthesis in whole animals. Administration of arsenite to rats for 10 days 

 led to a 27% decrease in liver arginase (Lightbody and Calvery, 1938) 

 and it is known that arsenite poisoning in man impairs the synthesis of 

 hemoglobin (Brugsch and Tichter, 1950), but in both instances the effect 



