ANALOGS OF NICOTINAMIDE 505 



nonicotinamide, and NADase (Johnson and McCoU, 1956). The NAD ana- 

 log was also detected spectroscopically in the livers and kidneys of treated 

 mice. This NAD analog is completely inactive with yeast alcohol dehydro- 

 genase. If the analyses of Shapiro et at. (1957) actually represent true NAD, 

 the small decreases observed following administration of 6-aminonicotina- 

 mide at 30 mg/kg for 3 days (14% in liver, 17% in adenocarcinoma, and 

 none in brain) would point to the NAD analog as being inhibitory to dehy- 

 drogenases. This explanation was accepted by Friedland et al. (1958) on 

 the basis of decreases in tissue ADP and ATP, as well as oxidative inhi- 

 bition. Although it has generally been assumed that the central effects of 

 6-aminonicotinamide are due to the formation of an abnormal NAD(P) ana- 

 log and to reduction in normal NAD(P), Redetzki and Alvarez- O'Bourke 

 (1962) found that the NAD level in the brain is only slightly depressed, 

 despite the rather marked decrease of liver NAD, and obtained no evidence 

 for the occurrence of an abnormal analog. The 6-aminonicotinamide analog 

 of NAD inhibits creatine kinase and pyruvate kinase noncompetitively, 

 about 40% depression occurring at 1 mM (von Bruchhausen 1964). It is 

 unlikely that these actions can be important in vivo unless these enzymes 

 are much more sensitive in intact cells. 



Administration of the analog to adenocarcinoma-bearing mice leads to 

 inhibition of certain enzymes determined in homogenates of the tumor: 

 lactate dehydrogenase is not affected, glyceraldehyde-3-P dehydrogenase is 

 inhibited 44%, the conversion of /?-hydroxybut>Tate to acetoacetate is in- 

 hibited 69%, and a-ketoglutarate oxidase is inhibited 83% (Dietrich et at., 

 1958). It was believed that the NAD analog is quite tightly bound to the 

 apoenzymes and prevents the combination with NAD. 



6-Aminonicotinamide exerts a depressing action against the growth of 

 certain lymphosarcomas and adenocarcinomas, and this is reversed by nic- 

 otinamide (Halliday et al., 1957). Tumor regression occurs at 3-4 mg/kg/ 

 day but some weight loss also occurs; at lower doses the weight loss can 

 be minimized with some reduction in carcinostatic activity, but combined 

 at these lower doses with 8-azaguanine it is reasonably effective (Shapiro 

 et al., 1957). It was considered to represent a new class of potentially useful 

 carcinostatic agents. It is interesting that 6-aminonicotinate is one-seventh 

 to one-fifteenth as toxic as the amide, suggesting either that penetration 

 of the acid is Kmiting or that conversion to the amide is slow. 



Inhibition of NAD(P) Enzymes by Various Nucleotides 

 and Related Substances 



The study of these inhibitions has three major purposes: (1) to obtain 

 information on the nature of the active centers and the binding groups of 

 the coenzymes, (2) to understand better the mutual relationships between 

 these naturally occurring substances and the possible regulatory effects 



