A putative metabolite of serotonin, tryptamine-4,5-dione, is an irreversible inhibitor of tryptophan hydroxylase: Possible relevance to the serotonergic neurotoxicity of methamphetamine

Citation
Mz. Wrona et G. Dryhurst, A putative metabolite of serotonin, tryptamine-4,5-dione, is an irreversible inhibitor of tryptophan hydroxylase: Possible relevance to the serotonergic neurotoxicity of methamphetamine, CHEM RES T, 14(9), 2001, pp. 1184-1192
Citations number
65
Categorie Soggetti
Pharmacology & Toxicology
Journal title
CHEMICAL RESEARCH IN TOXICOLOGY
ISSN journal
0893228X → ACNP
Volume
14
Issue
9
Year of publication
2001
Pages
1184 - 1192
Database
ISI
SICI code
0893-228X(200109)14:9<1184:APMOST>2.0.ZU;2-9
Abstract
Tryptamine-4,5-dione (T-4,5-D) is formed as a result of oxidation of 5-hydr oxytryptamine by superoxide (O-2(-).), nitric oxide (NO .), and peroxynitri te (ONOO-). T-4,5-D rapidly inactivates tryptophan hydroxylase (TPH), deriv ed from rat brain, probably as a result of covalent modification of active site cysteine residues. The activity of TPH exposed to T-4,5-D cannot be re stored by anaerobic reduction with dithiothreitol (DTT) and ferrous iron (F e2+) indicating that the inactivation is irreversible. 7-S-Glutathionyl-try ptamine-4,5-dione, formed by the rapid reaction between T-4,5-D and glutath ione, also inhibits TPH but in this case the activity is restored by anaero bic reduction with DTT/Fe2+. The results of this investigation may be relev ant to the initial reversible and subsequent irreversible inactivation of T PH evoked by methamphetamine and 3,4-methylenedioxymethamphetamine.