Putative oxidative metabolites of 1-methyl-6-hydroxy-1,2,3,4-tetrahydro-beta-carboline of potential relevance to the addictive and neurodegenerative consequences of ethanol abuse
Abstract
Ethanol is metabolized in the brain by catalase/H2O2 to yield acetaldehyde and by an ethanol-inducible form of cytochrome P450 (P450 IIE1) in a reaction that yields oxygen radicals. Within the cytoplasm of serotonergic axon terminals these metabolic pathways together provide conditions for the endogenous synthesis of 1-methyl-6-hydroxy-1,2,3,4-tetrahydro-beta-carboline (1), by reaction of acetaldehyde with unbound 5-hydroxytryptamine (5-HT), and for the oxygen radical-mediated oxidation of this alkaloid. The major initial product of the hydroxyl radical (HO.)-mediated oxidation of 1 in the presence of free glutathione (GSH), a constituent of nerve terminals and axons, is 8-S-glutathionyl-1-methyl-1,2,3,4-tetrahydro-beta-carboline-5,6-dione (6). When administered into the brains of mice, 6 is a potent toxin (LD50 = 2.9 microg) and evokes episodes of hyperactivity and tremor. Compound 6 binds at the GABA(B) receptor and evokes elevated release and turnover of several neurotransmitters. Furthermore, the GABA(B) receptor antagonist phaclofen attenuates the behavioral response caused by intracerebral administration of 6. These observations suggest that 6 might be an inverse agonist at the GABA(B) receptor site. Accordingly, it is sp...Continue Reading
References
Immunostained serotonergic fibers are decreased in selected brain regions of alcohol-preferring rats
Ethanol drinking following 6-OHDA lesions of nucleus accumbens and tuberculum olfactorium of the rat
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