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

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.