138 



1. MALONATE 



Effects on the Formation of Acetoacetate and Other Ketones 



It was known before 1912 that acetate, oxalate, and maleate can either 

 be metabolized to acetoacetate or so alter metabolism that acetoacetate ac- 

 cumulates, and for this reason Momose (1914) in Berlin studied the effects 

 of malonate perfused through starved dog livers at a concentration of 

 approximately 13 mM. He found that acetone appears and detected a sub- 

 stance which he only later, after returning to Japan (Momose, 1925), proved 

 was acetoacetate. However, he postulated that malonate -^ acetate — >■ 

 acetoacetate -^ acetone, which was not unreasonable considering the inhi- 

 bitory action of malonate was unknown. The appearance of acetone in the 

 urine of rabbits fed malonate or rats injected subcutaneously with malonate 

 was observed by Huszak (1935), and simultaneously Annau (1935) dem- 

 onstrated that malonate causes the formation of acetone in slices and 

 breis of rabbit kidney. Acetoacetate has been shown to accumulate in 

 tissues as a response to malonate (see accompanying tabulation). Since 

 acetoacetate and acetone are the most important ketonic substances ap- 

 pearing in the tissues, these results clearlj^ show that malonate is ketogenic. 



Acetoacetate is an important substance in intermediary metabolism and 

 the pathways for its formation and utilization are often complex. The con- 

 centration of acetoacetate will depend on the relative rates of its formation 

 and utilization. The accumulation of acetoacetate in the presence of mal- 

 onate could result from either an acceleration of its formation or an inhibi- 

 tion of its utilization, or both. The earliest concept that malonate itself 

 gives rise to the acetoacetate was soon abandoned, and several investigators 

 assumed that malonate interferes with the disposal of acetoacetate, while 



