Mechanisms of the Pellagragenic Effect of Leucine: Stimulation of Hepatic Tryptophan Oxidation by Administration of Branched-Chain Amino Acids to Healthy Human Volunteers and the Role of Plasma Free Tryptophan and Total Kynurenines

Abstract

The pellagragenic effect of leucine (Leu) has been proposed to involve modulation of L-tryptophan (Trp) metabolism along the hepatic kynurenine pathway. Here, we discuss some of the mechanisms suggested and report the effects in healthy volunteers of single doses of Leu (4.05–6.75 g) administered in a 16-amino acid mixture on concentrations of plasma Trp and its kynurenine metabolites. Flux of Trp through Trp 2,3-dioxygenase (TDO) is dose-dependently enhanced most probably by Leu and can be attributed to TDO activation. Trp oxidation is better expressed using plasma total kynurenines, rather than kynurenine, and free, rather than total, Trp. Increased hepatic Trp oxidation may be an additional mechanism of action of branched-chain amino acids in the acute Trp depletion test. Inhibition of intestinal absorption or hepatic uptake of Trp by Leu can be excluded. Potential mechanisms of the aggravation of pellagra symptoms by Leu are discussed.