Assessment of the Human Kynurenine Pathway: Comparisons and Clinical Implications of Ethnic and Gender Differences in Plasma Tryptophan, Kynurenine Metabolites, and Enzyme Expressions at Baseline and after Acute Tryptophan Loading and Depletion

Abstract

Tryptophan (Trp) metabolism via the kynurenine pathway (KP) was assessed in normal healthy US volunteers at baseline and after acute Trp depletion (ATD) and acute Trp loading (ATL) using amino acid formulations. The hepatic KP accounts for ~90% of overall Trp degradation. Liver Trp 2,3-dioxygenase (TDO) contributes ~70% toward Trp oxidation, with the remainder achieved by subsequent rate-limiting enzymes in the KP. TDO is not influenced by a 1.15 g Trp load, but is maximally activated by a 5.15 g dose. We recommend a 30 mg/kg dose for future ATL studies. ATD activates TDO and enhances the Trp flux down the KP via its leucine component. Higher plasma free [Trp] and lower total [Trp] are observed in women, with no gender differences in kynurenines. Kynurenic acid is lower in female Caucasians, which may explain their lower incidence of schizophrenia. African-American and Hispanic women have a lower TDO and Trp oxidation relative to free Trp than the corresponding men. African-American women have a potentially higher 3-hydroxyanthranilic acid/anthranilic acid ratio, which may protect them against osteoporosis. Future studies of the KP in relation to health and disease should focus on gender and ethnic differences.