INFLUENCE OF GLUTATHIONE ON THE OXIDATION OF METHYL-6-HYDROXY-1,2,3,4-TETRAHYDRO-BETA-CARBOLINE - CHEMISTRY OF POTENTIAL RELEVANCE TO THE ADDICTIVE AND NEURODEGENERATIVE CONSEQUENCES OF ETHANOL ABUSE

Recent evidence suggests that intraneuronal metabolism of ethanol by c atalase/H2O2 and an ethanol-inducible form of cytochrome P450 together generate acetaldehyde and oxygen radicals including the hydroxyl radi cal (HO.). Within the cytoplasm of serotonergic neurons, these metabol ic processes would thus provide acetaldehyde, which would react with u nbound 5-hydroxytryptamine (5-HT) to give methyl-6-hydroxy-1,2,3,4-tet rahydro-beta-carboline (1), known to be formed at elevated levels in t he brain following ethanol drinking, and HO. necessary to oxidize this alkaloid. In this study, it is demonstrated that the HO.-mediated oxi dation of 1 at physiological pH yields methyl-1,2,3,4-tetrahydro-beta- carboline-5,6-dione (8) that reacts avidly with free glutathione (GSH) , a significant constituent of axons and nerve terminals, to give dias tereomers of methyl-1,2,3,4-tetrahydro-beta-carboline-5,6-dione (9A an d 9B). In the presence of free GSH, ascorbic acid, other intraneuronal antioxidants/reductants, and molecular oxygen diastereomers, 9A/9B re dox cycle in reactions that generate H2O2 and, via trace transition me tal ion catalyzed decomposition of the latter compound, HO.. Further r eactions of 9A/9B with GSH and/or HO. generate several additional glut athioxyl conjugates that also redox cycle in the presence of intraneur onal reductants and molecular oxygen forming H2O2 and HO.. Thus, intra neuronal formation of 1 and HO. as a consequence of ethanol drinking a nd resultant endogenous synthesis of 8, 9A, and 9B would, based on the se in vitro chemical studies, be expected to generate elevated fluxes of H2O2 and HO. leading to oxidative damage to serotonergic axons and nerve terminals and the irreversible loss of GSH, both of which occur in the brain as a consequence of ethanol drinking. Furthermore, defici encies of 5-HT and loss of certain serotonergic pathways in the brain have been linked to the preference for and addiction to ethanol.