120 III. OXIDATION AND METABOLISM 



Unsaturated fatty acids have also been found to be ketogenic. These 

 include crotonic acid (CIInCH : Cli • COOH), as demonstrated by Blunden^oi 

 with fasting rats,N and by Jo wett and Quastel"'^ with liver slices, vinylacetic 

 acid (CH2:CH-CH2-COOH), as proved by Kleinzellcr/«5 who employed 

 liver slices from fasted pigeons and rats, and sorbic acid (CH3CH : CH • CH :- 

 CH-COOH), as proved by Cohen ^"^ and by Witter ct al}^ with liver slices, 

 and by Deuel ct al.^'^ in vivo in fasting rats. 



(b) Formation from Acetic Acid. There seems to be no doubt that two 

 acetic acids or two molecules closely related to acetate can condense to yield 

 acetoacetate by the following scheme: 



O 



CHs-COiOHT'HjCH.COOH > CHs-CCH.-COOH + H.O 



The formation of ketone bodies from acetate is supported by the demonstra- 

 tion of an increased ketonuria when acetate is fed to phlorhizmized dogs,^" 

 and by the finding of Loeb-^- and of Friedmann^- that abundant ketone 

 formation resulted from the perfusion of surviving liver with acetate. 

 Moreover, Swendseid, Barnes et al}^ showed by the use of carboxyl-labeled 

 acetic acid that ketone bodies may form by the condensation of acetate 

 molecules. In many additional experiments^^ '^^^ longer-chain fatty acids 

 labeled only in the carboxyl group have been shown to give rise to aceto- 

 acetate having an isotopic carbonyl carbon ; this could result only from its 

 synthesis from acetic acid molecules. Finally, a number of reports have 

 demonstrated that ketogenesis occurs in liver slices in which acetate is the 

 substrate. ^-•^''^ All of these investigations point to the fact that acetate 

 may serve as a building stone for acetoacetate, although it is not so effective 

 as butyric acid or longer even-chain fatty acids. This has been discussed 

 fully in the section on the synthesis of fatty acids (see pages 11 to 26), 

 and in the discussion of the (8-oxidation-acetic acid condensation theory 

 (see pages 83-87). However, there are negative reports in regard to this 

 condensation as, for example, that of Schultz and Smith. -'^^ These workers 

 were unable to demonstrate any significant changes in the blood ketones in 

 fasted, non-fasted, or phlorhizinized goats following the oral or hitra venous 

 administration of acetate, although butyric acid produced a rapid and im- 

 mediate rise in blood ketones, and caproic, caprylic, and capric acids caused 

 an increase in blood ketones after one hour. 



(c) Formation from Butyric Acid. Although the majority of the experi- 

 mental evidence favors the idea that butyric acid is converted solely to 



2«2 A. Loeb, Biochem. Z., 47, 118-126 (1912). 



283 L. H. Schultz and V. R. Smith, /. Dairy Sci., 32, 817-822 (1949). 



