VARIOUS METABOLIC PATHWAYS 691 



the arsenical concentration. Of course, there are a number of other reactions 

 forming acetyl-CoA (e. g., from the ketogenic amino acids) and utihzing 

 acetyl-CoA (e. g., the synthesis of sterols), and these must also be taken 

 into account. 



Fatty acids 



Pyruvate ^ >- Acetyl-CoA ^ — »- Cycle 



The synthesis of cholesterol from acetate is strongly inhibited by arsenite 

 but there is some disagreement as to the major sites of actions. The con- 

 version of mevalonate — »■ cholesterol is moderately sensitive, being de- 

 pressed 75-90% by 1 mM arsenite (Moller and Tchen, 1961; Gaylor, 1963), 

 as is the conversion of mevalonate -* squalene. The conversion of squa- 

 lene ^- sterols is not much affected by arsenite (Goodman, 1961; Moller and 

 Tchen, 1961). There appear to be two sensitive sites in this portion of the 

 sequence. One of these is on the pathway from mevalonate -^ squalene; 

 the site of attack is not on the reaction of 5-P-mevalonate — > 5-PP-meva- 

 lonate (Hellig and Popjak, 1961), or the reaction of farnesyl-PP -^ squa- 

 lene (Goodman and Popjak, 1960). The other sensitive site lies between 

 lanosterol and cholesterol. Moller and Tchen (1961) claimed that arsenite 

 causes the accumulation of radioactivity from mevalonate-2-C^'* in lanos- 

 terol during incubation with a rat liver homogenate, whereas Gaylor 

 (1963) found the radioactivity to appear mainly in lanosta-7,24-dien-3/?-ol 

 when rat epidermis is used, the labeling of lanosterol not being altered. 

 Moller and Tchen (1961) believe that the most sensitive step is the oxidation 

 of lanosterol. It is interesting that the inhibition of cholesterol formation 

 is enhanced by equimolar dimercaprol and no reversal of the inhibition is 

 seen with 10-fold excess dimercaprol (Gaylor, 1963). This might be taken 

 by some as evidence for vicinal SH groups in one or more of the enzymes 

 involved. The synthesis of corticoids by rat adrenal sections seems to be 

 less sensitive to arsenite than is the synthesis of cholesterol, about 75% 

 inhibition being exerted by 1 milf arsenite (Schonbaum et al., 1956). 

 Unfortunately, there has been no conclusive work on the effects of arsenicals 

 on the formation of mevalonate from acetate or acetyl-CoA, and it may 

 well be that additional sensitive sites lie in this portion of the pathway. 

 On the basis of these results one might expect to find a depression of choles- 

 terol levels in vivo, but such is not the case. Auken (1945) reported that 



