Inhibition of rat liver tryptophan pyrrolase activity and elevation of brain tryptophan concentration by administration of DL-alpha-amino-beta-pyridinepropanoic acid (pyridylalanine) analogs.
Single doses of DL-alpha-amino-beta-(2-pyridine)propanoic acid (2-PA, 100 mg/kg) significantly decreased the holoenzyme and apoenzyme activities of rat liver tryptophan pyrrolase (TP) and increased brain tryptophan, 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-alpha-amino-beta-(3-pyridine)propanoic acid (3-PA, 100 mg/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-alpha-Amino-beta-(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 (100 mg/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.
Shimeno
H
H
Faculty of Pharmaceutical Sciences, Fukuoka University, Japan.
Bou
S
S
Harada
N
N
Toda
A
A
Nagamatsu
A
A
D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D012701:Serotonin / Q000378:metabolism; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000378:metabolism*; D014366:Tryptophan Oxygenase / Q000037:antagonists & inhibitors*
C051999:3-(3-pyridyl)alanine; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D014364:Tryptophan; D014366:Tryptophan Oxygenase; D000409:Alanine