150 



1. MALONATE 



and liver slices showed impaired respiration with succinate, acetate, and 

 acetoacetate as substrates. This augmentation of tissue cholesterol is clear 

 and is reasonable on the basis of diversion of acetyl-CoA metabolism by a 

 block of succinate oxidase. However, in vitro work has shown only inhibi- 

 tion of cholesterol synthesis. The formation of labeled cholesterol from 

 octanoate-1-C^* in rat liver slices is consistently depressed by 5.84 mM 

 malonate, and fumarate was very ineffective in counteracting this inhibition 

 (Lyon and Geyer, 1954). The total lipids rise and this is partly attributable 

 to the increased synthesis of short-chain fatty acids. The formation of 

 labeled cholesterol from acetate- l-C^* in the same tissue is inhibited 73% 

 by 50 mM malonate (Kline and DeLuca, 1956) and 78% by 30 mM mal- 

 onate (van Vals and Emmelot, 1957). Cholesterol synthesis in rat tumors is 

 even more strongly depressed. The discrepancy between the in vivo and in 

 vitro results might be due to several factors. In the intact animal many 

 secondary effects may occur, e.g. as a result of the marked rise in blood 

 glucose. Also the malonate concentration in the tissues of the rats is undoubt- 

 edly less than in the work with slices. It is unfortunate that most of the 

 studies have been made with unreasonably high malonate concentrations 

 so that a specific inhibition of succinate oxidation is doubtful. The catabolism 

 of cholesterol, as determined by the formation of C^'^Og from the labeled 

 terminal methyl groups of cholesterol, in suspensions of rat liver mitochon- 

 dria is inhibited 78% by 10 mM malonate (Whitehouse et al., 1959), so 

 that this factor must also be considered in explaining changes in tissue levels 

 over longer periods of time. The synthesis of other sterols has been studied 

 very little. Pieces of rat adrenal form corticosteroids in the presence of 

 glucose and this is markedly stimulated by the addition of ACTH. Malonate 

 at 10 mM stimulates the formation of sterols in the absence of ACTH 

 from 17 to 22 //g/100 mg/2 hr ( + 29%) but depresses the synthesis in the 

 ACTH-activated preparations from 81 to 72 //g/100 mg/2 hr (-11%) 

 (Schonbaum et al., 1956). Fluoroacetate also inhibits very little and it was 

 concluded that the cycle does not play a major role in sterol synthesis, 

 glucose metabolism and particularly the pentose phosphate pathway being 

 of more importance. The bearing of such studies on the metabolic basis of 

 cholesterol and hormonal sterol levels in animals, especially the relationship 



