324 VII. ACIDS, AMIDES, ALDEHYDES AND HYDROCARBONS 



terol.'^^ Another indication that squalene is an intermediate in the syn- 

 thesis of cholesterol from acetate is the finding that feeding squalene to 

 rats for two days leads to a nearly complete suppression of the acetate -»■ 

 cholesterol transformation, concomitantly with an increase in liver sterols.^" 



On the other hand, some negative evidence in regard to the hypothesis 

 that squalene is an intermediate in cholesterol synthesis has been adduced. 

 Thus, Tomkins et al}^^ were miable to demonstrate the in vitro or in vivo 

 conversion of syiithetically-prepared squalene into cholesterol by the liver. 

 There was some evidence of its oxidation to COo. However, in a later 

 study by Tomkins and co-workers, ^^^ in which natural squalene was fed 

 for nine days, in place of regenerated squalene, a marked reduction in the 

 conversion of the added C^^. to cholesterol resulted. This leads these 

 authors to conclude that natural squalene is a cholesterol precursor. 

 Although Popjak^®" demonstrated the biosynthesis of both squalene and 

 cholesterol from acetate-1-C^* by the liver slices of the rat and by the 

 ovarian tissues of the laying hen, the relationship of the specific activity 

 was believed to be such as to exclude squalene per se as the immediate pre- 

 cursor of cholesterol. Kritchevsky et al.^^^ likewise reported that squalene 

 does not induce a significant increase in atheroma, as does cholesterol, even 

 though it is believed to be an immediate precursor in the biosynthesis of 

 cholesterol. Schwenk, Todd, and Fish^^- isolated squalene-C^^ from the 

 extracts obtained from the livers of pigs previously perfused with C'^- 

 labeled acetate, which was converted by rats into cholesterol-C'^ after 

 intraperitoneal injection or after feeding. This was the first instance in 

 which squalene was isolated from a mammalian liver. The presence of a 

 number of intermediates of the acetate -^ cholesterol reaction in the non- 

 saponifiable fraction of the perfused livers was also observed. This evi- 

 dence is so overwhelming for the participation of squalene in the acetate -> 

 cholesterol reaction that one can accept it as a proven fact. For a further 

 discussion, see page 384. 



On the other hand, little is known concerning the metabolism of squalene, 

 other than its conversion to cholesterol and its probable oxidation to carbon 



"« R. G. Langdon and K. Bloch, /. Biol. Chem., 200, 135-144 (1953). 

 1" R. G. Langdon and K. Bloch, Federation Proc, 12, 235-236 (1953). 



158 G. M. Tomkins, I. L. Chaikoff, W. G. Dauben, H. L. Bradlow, and P. A. Srere, J. 

 Am. Chem. Soc, 74, 6145-6146 (1952). 



159 G. M. Tomkins, W. G. Dauben, H. Sheppard, and I. L. Chaikoff, /. Biol. Chem., 

 i^O^, 487-489 (1953). 



i«o G. Popjdk, Arch. Biochem. Biophys., 48, 102-106 (1954). 



1^1 D. Kritchevsky, A. W. Moyer, and W. C. Tesar, Arch. Biochem.. Biophys., 44, 241 

 (1953). 



162 E. Schwenk, D. Todd, and C. A. Fish, Arch. Biochem. Biophys., 49, 187-206 (1954). 



