Effects of Dietary 6-Aminonicotinamide, an Antagonist of Nicotinamide, on the Metabolism of Tryptophan to Nicotinamide in Rats

Abstract

It has been reported that pellagra is caused by abnormal metabolism of tryptophan, although it is generally believed that pellagra is caused by a deficiency of niacin. The administration of 6-aminonicotinamide (6-AN) to rats induces central nervous lesions being similar those seen in pellagra. So, we investigated the effects of 6-AN on the metabolism of tryptophan to nicotinamide. The threshold of the toxicity of 6-AN was around 0.001 % when it was incorporated in the diet. In enzyme activities involved in the metabolism of tryptophan to nicotinamide, the activities of tryptophan oxygenase and aminocarboxymuconatesemialdehyde decarboxylase were greatly increased, while that of kynureninase was decreased by feeding of 6-AN diets. In enzymes involved in catabolism of nicotinamide, the activity of nicotinamide methyltransferase was increased and those of N 1 -methyl-2-pyridone-5-carboxamide (2-Py)-and N1-methyl-4-pyridone-3-carboxamide (4-Py)-forming N1-methylnicotinamide (MNA) oxidases were decreased by feeding of 6-AN diets. These changes were similar those seen in alloxan-and streptozotocin-induced diabetic rats. The urinary excretion ratio of (2-Py +4-Py)fMNA, which is reported to be lower in pellagrins than in normals, was decreased, and the conversion ratio of tryptophan to nicotinamide was also decreased. These results demonstrated that the metabolism of tryptophan to nicotinamide was greatly changed by intake of 6-AN. In 1955, Johnson and McColl 1) first reported that 6-AN was the most potent known antagonist of Nam. 6-AN has central nervous system toxicity and the lesions in rats are similar to those seen in pellagra.2 ) It is generally believed that pellagra is caused by a niacin deficiency after Elvehjem et al. 3 . 4 ) reported in 1937 that NiA and Nam were highly effective in curing canine black tongue, which is a disease similar to human pellagra. In 1945, Krehl et al. 5 ) demonstrated that Trp could replace niacin in rat growth and now, the conversion pathway of Trp to niacin is established on the molecular level and is demonstrated to operate in humans. For example, Horwitt et al. 6 ) reported that 60 mg of Trp was consistent with 1 mg of niacin in humans. The fact that Trp is a precursor of niacin means that animals seldom get a niacin deficiency when the conversion ofTrp to niacin operates normally since animals contain a large quantity of Trp as body proteins. In fact, while humans were starved the urinary excretion of MNA increased,7) and in rats, the blood NAD content did not decrease while they were starved. 8 ) Therefore, some investigators, for example, Bender 9 ) and Salih et al. )consider that pellagra is induced by abnormal metabolism of Trp to niacin. Accordingly, it is possible that 6-AN affects the metabolism of Trp to niacin. In this paper, we investigated the effects of dietary 6-AN on the metabolism of Trp to niacin in rats. Materials and MethodsChemicals. NAD+ was purchased from the Sigma Chemical Company (St. Louis, MO, U.S.A.). Vitamin-free milk casein, sucrose, L-methio...