1. In order to investigate the mechanism of the pellagragenic action of excess dietary leucine, rats were fed on diets providing a minimally-adequate amount of tryptophan, with no preformed niacin, with and without the addition of 15 g leucine/kg diet. This amount of leucine in the diet has been demonstrated previously to lead to depletion of blood and liver nicotinamide nucleotides. The metabolism of tryptophan was assessed by measurement of the production of 14CO2 after the administration of [methylene-14C]tryptophan to estimate the activity of kynureninase (L-kynurenine hydrolase, EC 126.96.36.199) and [benzene ring U-14C]tryptophan to estimate the activity of picolinate carboxylase (aminocarboxymuconate semialdehyde decarboxylase, EC 188.8.131.52).
2. A dietary excess of leucine led to inhibition of kynureninase and increased the activity of picolinate carboxylase. Both of these effects would result in a reduction in the rate of metabolism of acroleylaminofumarate (aminocarboxymuconate semialdehyde) to quinolinic acid and hence to nicotinamide nucleotides. These two effects provide an explanation for the pellagragenic effect of a dietary excess of leucine in animals that are wholly or partly reliant on endogenous synthesis from tryptophan to meet their requirements for nicotinamide nucleotides, and presumably also explain the pellagragenic effect of a dietary excess of leucine in man.
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