XII. PHARMACOLOGY 573 



B. TOXICITY IN DIETS 



Handler and Dann^ found that inclusion of 1 % nicotinamide in a low 

 protein diet almost completely inhibited growth in rats. This growth in- 

 hibition could be prevented by methionine or by choline plus homocystine 

 but not by choline, betaine, homocystine, or cystine alone. One per cent 

 nicotinic acid in the same diet did not inhibit growth but did induce fatty 

 liver, an effect preventable by methionine, choline, and betaine but aggra- 

 vated by cystine or homocystine.^' ^° Randoin and Causeret'^ confirmed 

 the dietary toxicity of 0.5 to 2.0% nicotinamide but failed to obtain re- 

 versal with methionine. ^^ They did obtain reversal of toxicity with liver 

 powder or folic acid plus calcium pantothenate.'^ One or two per cent 

 nicotinamide in the diet of rabbits and guinea pigs did not depress growth 

 and did not cause fatty liver.'* It is of interest that the latter two species 

 do not methylate nicotinamide to any extent, whereas the rat does. Two 

 per cent nicotinamide reduced the growth of chicks but did not produce 

 fatty liver; neither glycine nor choline restored growth. Two per cent 

 nicotinic acid in this diet had no effect on chick growth. '■* 



Coulson and Brazda'^ fed rats a series of pyridine derivatives, including 

 the N'-methyl derivatives of each, at a level of 1 % in a high protein diet. 

 None of the N'-methyl derivatives affected liver fat. N'-Methylation had 

 no consistent effect when the growth depression obtained with methylated 

 compounds was compared with that obtained with non-methylated com- 

 pounds. 7-Picoline, nicotinic acid, and nicotinamide increased liver fat. 

 /S-Picohne and coramine produced larger increases in liver fat, but this 

 could be prevented by methionine or choline. Coramine produced a large 

 increase in fat-free liver weight which could not be prevented by choline 

 or methionine. These results suggest that the toxicity of pyridine deriva- 

 tives may be only partially explained by the fact that the tissues are robbed 

 of the methyl groups necessary for their methylation and excretion. 



C. CIRCULATION 



Nicotinic acid, 20 to 30 mg. given intravenously or 100 to 500 mg. orally, 

 produces a transient vasodilatation of the cutaneous vessels, particularly 

 of the ears, face, neck, upper extremities, and trunk in most human sub- 

 jects. The reaction is accompanied by itching, burning, and tingling of the 



9 P. Handler and W. J. Dann, /. Biol. Chem. 146, 357 (1942). 

 1" A. Aschkenasy and J. Mignot, Compt. rend. soc. biol. 140, 261 (1946). 



11 L. Randoin and J. Causeret, Compt. rend. 227, 367 (1948). 



12 L. Randoin and J. Causeret, Compt. rend. 228, 504 (1949) [C. A. 43, 6296 (1949)]. 



13 L. Randoin and J. Causeret, Compt. rend. 227, 399 (1948). 

 " P. Handler, J. Biol. Chem. 154, 2U3 (1944). 



15 R. A. Coulson and F. G. Brazda, Proc. Soc. Exptl. Biol. Med. 65, 1 (1947). 



