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-hydroxytryptamine by superoxide (O(2)(-)(*), nitric oxide (NO*), and peroxynitrite (ONOO(-)). T-4,5-D rapidly inactivates tryptophan hydroxylase (TPH), derived 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 restored by anaerobic reduction with dithiothreitol (DTT) and ferrous iron (Fe(2+)) indicating that the inactivation is irreversible. 7-S-Glutathionyl-tryptamine-4,5-dione, formed by the rapid reaction between T-4,5-D and glutathione, also inhibits TPH but in this case the activity is restored by anaerobic reduction with DTT/Fe(2+). The results of this investigation may be relevant to the initial reversible and subsequent irreversible inactivation of TPH evoked by methamphetamine and 3,4-methylenedioxymethamphetamine.
Wrona
M Z
MZ
Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, USA.
Dryhurst
G
G
D000818:Animals; D001921:Brain / Q000201:enzymology / Q000502:physiology; D000697:Central Nervous System Stimulants / Q000494:pharmacology / Q000633:toxicity*; D002851:Chromatography, High Pressure Liquid; D045563:Indolequinones; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology / Q000633:toxicity*; D016877:Oxidants; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D014363:Tryptamines / Q000737:chemistry / Q000494:pharmacology*; D014365:Tryptophan Hydroxylase / Q000187:drug effects* / Q000378:metabolism*
D000697:Central Nervous System Stimulants; D045563:Indolequinones; D016877:Oxidants; D014363:Tryptamines; C060213:tryptamine-4,5-dione; D008694:Methamphetamine; D014365:Tryptophan Hydroxylase