EFFECTS ON LIPID 'METABOLISM 145 



The most reliable work is the demonstration of the inhibition of incor- 

 poration of C^'* into lipids. Thus the formation of labeled fatty acids from 

 acetate-1-C^^ in various tumors is inhibited by 0.54 mM iodoacetate, al- 

 though to very different degrees, and never as much as the incorporation 

 into cholesterol, proteins, or CO2 (van Vals and Emmelot, 1957). The in- 

 corporation of label from glucose-C^^ should be more potently inhibited, 

 and in mammary gland 0.1 mM iodoacetate reduces lipid labeling around 

 65% (McLean, 1962). Lynen (1959) showed that the reaction of acetyl- 

 CoA with CO2 and ATP, catalyzed by a yeast enzyme, is blocked by 10 mM 

 iodoacetamide at the level of malonyl-CoA, and concluded that iodoacet- 

 amide would block synthesis of lipid from malonyl-CoA (the unfortunately 

 high concentration must be noted). Vagelos and Alberts (1960) also showed 

 that the enzyme catalyzing the reaction 



Malonyl-CoA + R— CO— CoA ±i CO^ + R— CO— CH^— CO— CoA + CoA 



in Clostridium Huyveri is quite strongly inhibited by iodoacetate and iodo- 

 acetamide. Thus McLean suggested that the effects of iodoacetate on mam- 

 mary gland may be primarily on the utilization of two-carbon units for 

 lipid synthesis rather than on the formation of the two-carbon units. 



Sterol synthesis is very sensitive to iodoacetate. In microsomal and super- 

 nate fractions from rat liver the incorporation of acetate- 1-C^^ into choles- 

 terol is inhibited 53% by 0.02 mM iodoacetate (Bucher and McGarrahan, 

 1956). The authors felt that the synthesis is dependent on glycolysis for 

 the supply of ATP and that iodoacetate blocks here, but did not show that 

 ATP would counteract the inhibition. The formation of corticoids in rat 

 adrenal when stimulated by ACTH is inhibited some 70% by 1 mM iodo- 

 acetate and this is not altered by pyruvate (Schonbaum et al, 1956). Since 

 the cycle is not important and the pentose-P pathway is very active, it ap- 

 pears that sterol synthesis is affected directly. Later steps in sterol genesis 

 may be sensitive to iodoacetate. Thus the incorporation of mevalonate-C^^ 

 in Lactobacillus casei is inhibited 54% by 1 mM iodoacetate (Thorne and 

 Kodicek, 1962), the incorporation of Zl^-isopentenyl-PP into lycopene in 

 tomato homogenates is blocked completely by 5.4 mM iodoacetamide (Var- 

 ma and Chichester, 1962), the conversion of farnesyl-PP to squalene in liver 

 microsomes is inhibited 12% by 1 mM iodoacetamide (Anderson et al, 

 1960), and the formation of labeled sterol from squalene-Ci* in liver is re- 

 duced 46% by 0.42 mM iodoacetamide (Goodman, 1961). Thus there is 

 sufficient evidence that these inhibitors may depress sterol synthesis at 

 several points. Once the sterols are formed, their interconversions are prob- 

 ably not sensitive to iodoacetate; at least oxidations and hydroxylations 

 are quite resistant. 



The synthesis of phospholipids has frequently been studied by measuring 

 the incorporation of P^'^ into various fractions. The problem with cellular 



