Molecular Insights into the Interaction of Tryptophan Metabolites with the Human Aryl Hydrocarbon Receptor : Tryptophan as Antagonist and no Direct Involvement of Kynurenine.

Background: A direct link between the tryptophan (Trp) metabolite kynurenine (Kyn) and the aryl hydrocarbon receptor (AhR) is not supported by metabolic considerations and by studies demonstrating the failure of Kyn concentrations of up to 100 μM to activate the receptor in cell culture systems using the proxy system of cytochrome 450-dependent metabolism. The Kyn metabolite kynurenic acid (KA) activates the AhR and may mediate the Kyn link. Recent studies demonstrated down regulation and antagonism of activation of the AhR by Trp.

Kynurenine pathway of tryptophan metabolism in pathophysiology and therapy of major depressive disorder.

Serotonin deficiency in major depressive disorder (MDD) has formed the basis of antidepressant drug development and was originally attributed to induction of the major tryptophan (Trp)-degrading enzyme, liver Trp 2,3-dioxygenase (TDO), by cortisol, leading to decreased Trp availability to the brain for serotonin synthesis. Subsequently, the serotonin deficiency was proposed to involve induction of the extrahepatic Trp-degrading enzyme indoleamine 2,3-dioxygenase (IDO) by proinflammatory cytokines, with inflammation being the underlying cause. Recent evidence, however, challenges this latter concept, as not all MDD patients are immune-activated and, when present, inflammation is mild and/or transient.

Inflammation and serotonin deficiency in major depressive disorder: molecular docking of antidepressant and anti-inflammatory drugs to tryptophan and indoleamine 2,3-dioxygenases.

The roles of the kynurenine pathway (KP) of tryptophan (Trp) degradation in serotonin deficiency in major depressive disorder (MDD) and the associated inflammatory state are considered in the present study. Using molecular docking in silico, we demonstrate binding of antidepressants to the crystal structure of tryptophan 2,3-dioxygenase (TDO) but not to indoleamine 2,3-dioxygenase (IDO). TDO is inhibited by a wide range of antidepressant drugs.

Docking studies of antidepressants against single crystal structure of tryptophan 2, 3-dioxygenase using Molegro Virtual Docker software.

Tryptophan 2, 3-dioxygenase (TDO) a heme containing enzyme found in mammalian liver is responsible for tryptophan (Trp) catabolism. Trp is an essential amino acid that is degraded in to N-formylkynurenine by the action of TDO. The protein ligand interaction plays a significant role in structural based drug designing.

Serotonergic mediation effects of St John's wort in rats subjected to swim stress.

Present study shows the effects of St John's Wort (SJW) (20 mg/kg) on swim stress induced changes in tryptophan (TRP) metabolism and disposition in rats. The results show that after forced swim test (FST) hepatic tryptophan pyrrolase (holo and total) activities were significantly decreased (P<0.001).

Brain tryptophan metabolism remained unaltered in restraint stressed rats following fluoxetine administration.

Effects of two hours immobilization stress on tryptophan (Tp) metabolism in rats was studied following fluoxetine-HCl (20 mg/kg) administration. After 2 hr immobilization stress there was no effect on peripheral liver Tp metabolism but there was marked increase in brain Tp metabolism leading to increases in 5-HT (5-Hydroxy tryptamine) synthesis and turn over. Rats subjected to 2 hrs immobilization stress immediately after fluoxetine-HCl (20 mg/kg) administrations show significant increases in holo and total Tp pyrrolase enzyme activities leading to decreased serum total Tp concentrations.

Increases in brain tryptophan concentration in stressed rats following ethanol administration.

Objective: To determine the effect of acute ethanol administration on tryptophan metabolism in stressed and unstressed rats.

Design: Phase I clinical trial.

Place And Duration Of Study: Department of Biochemistry, University of Karachi.