Inhibition of rat Liver Tryptophan Pyrrolase Activity and Elevation of Brain Tryptophan Concentration by Administration of DL-α-Amino-β-Pyridinepropanoic Acid (Pyridylalanine) Analogs

Abstract

Single doses of DL-α-amino-β-(2-pyridine)propanoic acid (2-PA, 100mg/kg) significantly decreased the holoenzyme and apoenzyme activities of rat liver tryptophan pyrrolase (TP) and increased brain trypto-phan, serotonin (5-HT) and 5-hydroxyindole-3-ylacetic acid concentrations. 2-PA had no inhibitory effect on either of the enzyme activities in vitro, but its expected metabolites were effective. Single doses of DL-α-amino-β-(3-pyridine)propanoic acid (3-PA, 100mg/kg) decreased only the holoenzyme activity and elevated brain tryptophan and its metabolites levels in rats. 3-PA and its metabolite, 3-pyridylpyruvate, inhibited only the holoenzyme activity in vitro. DL-α-Amino-β-(4-pyridine)propanoic acid (4-PA) caused significant changes in liver TP (holo-and apoenzyme forms) activity and brain tryptophan concentration only after repeated administration (100mg/kg/day). 4-PA was a weak inhibitor of the holoenzyme, but its metabolites apparently inhibited the holo-and apoenzyme activities in vitro. These findings suggest that PA analogs (and/or their metabolites) increased brain tryptophan (and hence 5-HT synthesis) by directly inhibiting liver TP activity.

Key Words: :

• DL-α-Amino-β-pyridinepropanoic acid analogs
• liver tryptophan pyrrolase inhibition
• increases in brain tryptophan and serotonin