Effects of a dietary excess of leucine and of the addition of leucine and 2-oxo-isocaproate on the metabolism of tryptophan and niacin in isolated rat liver cells.

1. Feeding rats on a low-tryptophan, niacin-free, high-leucine diet resulted in impaired synthesis from tryptophan of the nicotinamide nucleotide coenzymes, NAD and NADP, and N1-methyl nicotinamide in isolated hepatocytes, compared with cells from animals fed on a low-tryptophan, niacin-free control diet providing an appropriate amount of leucine. This was accompanied by reduced accumulation of the tryptophan metabolites kynurenine, 3-hydroxykynurenine and xanthurenic acid. 2. With hepatocytes from animals fed on the low-tryptophan, niacin-free control diet, the addition of leucine to the incubation medium resulted in reduced synthesis of niacin from tryptophan, and a small increase in the accumulation of 3-hydroxykynurenine. 3. With hepatocytes from animals fed on the low-tryptophan, niacin-free control diet, the addition of 2-oxoisocaproate to the incubation medium resulted in increased synthesis of NAD(P) and niacin, and increased accumulation of 3-hydroxykynurenine. 4. The results suggest that a dietary excess of leucine alters the activity of the enzymes of tryptophan----niacin metabolism, or the uptake of tryptophan into the liver, in a different manner from the simple inhibition and activation seen in experiments in vitro. 5. Differences between studies in isolated hepatocytes and intact animals suggest that extra-hepatic metabolism of tryptophan, catalysed by indoleamine dioxygenase, is more important than has been believed hitherto.