INFLUENCE OF L-CYSTEINE ON THE OXIDATION CHEMISTRY OF SEROTONIN

L-Cysteine (CySH) intervenes in the normal electrochemically driven ox idation of 5-hydroxytryptamine (5-HT; serotonin) at physiological pH b y scavenging the quinone imine proximate oxidation product of this ind olic neurotransmitter to give 4-S-cysteinyl-5-hydroxy-tryptamine (4-S- CyS-5-HT). The latter cysteinyl conjugate is more easily electro-oxidi zed than 5-HT and, in the presence of free CySH, undergoes a complex s eries of reactions leading to minoethyl)-1,2,3,5,6,9-hexahydro-5,9-dio xo-pyrrolo [3, 2-g] [1, 4] benzothiazine-2-carboxylic acid (20) and N- [7-[(2-amino-2-carboxyethyl) )-1,4-dihydro-4-oxo-5H-indol-5-ylidene]-L -cysteine (4). CySH also reacts with another normal oxidation product of 5-HT, tryptamine-4,5-dione, to give 4 and 20. There is evidence tha t aberrant oxidative metabolism of 5-HT occurs in the brains of Alzhei mer's Disease patients. In the event that such reactions occur in the cytoplasm of serotonergic nerve terminals or axons they would necessar ily expose electrophilic intermediates and products to the intraneuron al nucleophiles CySH and GSH. The results of this study indicate that 4 and 20 might represent aberrant oxidative metabolites formed in such reactions. However, the ease of oxidation of 4-S-CyS-5-HT compared to 5-HT suggest that this conjugate is likely to be only a transient spe cies in vivo under conditions where the neurotransmitter is oxidized. (C) 1994 Academic Press, Inc.