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

Alcohol
M Z WronaG Dryhurst

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

Oct 1, 1992·Alcoholism, Clinical and Experimental Research·K GillR A Deitrich
Jul 7, 1992·Biochemical Pharmacology·C M AragonZ Amit
Jan 1, 1991·Psychopharmacology·J C FroehlichT K Li
Jul 1, 1991·Alcohol·L D ReidC L Hubbell
Nov 6, 1991·Biochemical Pharmacology·Z Fa, G Dryhurst
Dec 1, 1991·Pharmacology, Biochemistry, and Behavior·R D Myers, S D Quarfordt
Mar 1, 1991·Alcoholism, Clinical and Experimental Research·C M AragonZ Amit
Sep 1, 1990·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·J O PerssonM Ingelman-Sundberg
Feb 1, 1989·British Journal of Pharmacology·G BonannoM Raiteri
Jan 1, 1989·Life Sciences·A M Allan, R A Harris
Oct 1, 1989·Trends in Pharmacological Sciences·N Bowery
Aug 17, 1989·The New England Journal of Medicine·M E CharnessD A Greenberg
Jun 1, 1989·Drug and Alcohol Dependence·M UysalG Aykaç
Jun 1, 1989·Trends in Pharmacological Sciences·A DeBlasiH J Motulsky
Sep 1, 1987·Neuropharmacology·A K Mehta, M K Ticku
Jun 1, 1986·Pharmacology, Biochemistry, and Behavior·P Huttunen, R D Myers
Mar 3, 1987·Brain Research·D I KerrD R Curtis
Dec 1, 1988·Drug and Alcohol Dependence·B SjöquistS Lindén
Apr 21, 1987·Brain Research·A SlivkaG Cohen
Dec 1, 1974·Proceedings of the National Academy of Sciences of the United States of America·S R ZukinS H Snyder

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Citations

Apr 9, 2002·Journal of Toxicology and Environmental Health. Part a·Young-Joon SurhHye-Ran Yoon
Aug 16, 2001·Alcoholism, Clinical and Experimental Research·S M ZimatkinR A Deitrich
Aug 2, 2007·American Journal of Public Health·Michael RabinoffCandice Park
Jan 26, 2017·Neuropharmacology·Matthew T ReillyGeorge F Koob

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