VARIOUS METABOLIC PATHWAYS 689 



An action of arsenite generally ignored is the lowering of the coenzyme 

 A level. Estler et al. (1960) found that the coenzyme A in yeast is reduced 

 25% by 1.1 milf arsenite and 50% by 4.8 mM arsenite. Such an effect would 

 not only interfere further with keto acid oxidation, but should suppress 

 a variety of reactions. It is doubtful if reaction with other monothiols 

 is very important, and it has been shown that massive doses of neoarsphen- 

 amine are required in rabbits to lower tissue glutathione levels even slightly 

 (Brown and Kolmer, 1929). There may of course be, unknown thiols of 

 metabolic importance with which the arsenicals readily react. 



VARIOUS METABOLIC PATHWAYS 



Inasmuch as many pathways of metabolism are intimately related to 

 the formation and utilization of acetyl-CoA, and hence to keto acid oxi- 

 dation and the operation of the cycle, the arsenicals might be expected 

 to alter rather extensively the metabolic pattern indirectly in addition to 

 any direct effects they might have on these pathways. It is usually difficult 

 to distinguish between the primary and secondary effects in tissues or 

 whole animals, and it is probable on the basis of the information we have 

 that both always occur simultaneously. 



Lipid Metabolism 



It has been stated many times that arsenite administered in subtoxic 

 doses over a period of time increases assimilative processes through an 

 inhibition of oxidations, and that this can lead to an acceleration of growth 

 and increased body weight (see page 725). At certain dosage levels there 

 may be an increase in total body fat without significant change in the body 

 weight (Nakazawa, 1931); higher doses depress the food intake and cause 

 a loss of weight. Fatty degeneration of the liver during chronic arsenical 

 poisoning has been noted frequently, but accumulation of lipid occurs in 

 many tissues, even in cartilage cells (Tinacci, 1952) and the perfused rabbit 

 heart (Tanzi, 1938).* The effects of the arsenicals on lipid metabolism 

 must be very complex and no detailed study of this has yet been made. 



It was assumed by the early workers that arsenicals depress lipid cata- 



* Fatty degeneration or infiltration of tissues has often been taken as evidence 

 for an increased lipid content, but this is not necessarily true since histologically 

 the fat may become more visible, due to profound changes in cytoplasmic structure, 

 without marked alterations in total content. Thus rabbit livers exhibiting severe 

 necrosis and fatty degeneration due to arsphenamine administration show relatively 

 minor changes in lipid composition, there being possibly a slight rise in cholesterol 

 and some decrease in neutral fats (MacLachlan, 1940). 



