Alpha-thujone (the active component of absinthe): gamma-aminobutyric acid type A receptor modulation and metabolic detoxification.
Alpha-thujone is the toxic agent in absinthe, a liqueur popular in the 19th and early 20th centuries that has adverse health effects. It is also the active ingredient of wormwood oil and some other herbal medicines and is reported to have antinociceptive, insecticidal, and anthelmintic activity. This study elucidates the mechanism of alpha-thujone neurotoxicity and identifies its major metabolites and their role in the poisoning process. Four observations establish that alpha-thujone is a modulator of the gamma-aminobutyric acid (GABA) type A receptor. First, the poisoning signs (and their alleviation by diazepam and phenobarbital) in mice are similar to those of the classical antagonist picrotoxinin. Second, a strain of Drosophila specifically resistant to chloride channel blockers is also tolerant to alpha-thujone. Third, alpha-thujone is a competitive inhibitor of [(3)H]ethynylbicycloorthobenzoate binding to mouse brain membranes. Most definitively, GABA-induced peak currents in rat dorsal root ganglion neurons are suppressed by alpha-thujone with complete reversal after washout. alpha-Thujone is quickly metabolized in vitro by mouse liver microsomes with NADPH (cytochrome P450) forming 7-hydroxy-alpha-thujone as the major product plus five minor ones (4-hydroxy-alpha-thujone, 4-hydroxy-beta-thujone, two other hydroxythujones, and 7,8-dehydro-alpha-thujone), several of which also are detected in the brain of mice treated i.p. with alpha-thujone. The major 7-hydroxy metabolite attains much higher brain levels than alpha-thujone but is less toxic to mice and Drosophila and less potent in the binding assay. The other metabolites assayed are also detoxification products. Thus, alpha-thujone in absinthe and herbal medicines is a rapid-acting and readily detoxified modulator of the GABA-gated chloride channel.
Höld
K M
KM
Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, 114 Wellman Hall, University of California, Berkeley, CA 94720-3112, USA.
Sirisoma
N S
NS
Ikeda
T
T
Narahashi
T
T
Casida
J E
JE
D018646:Absinthe / Q000032:analysis*; D000818:Animals; D000081008:Bicyclic Monoterpenes; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D018118:Chloride Channels / Q000187:drug effects / Q000502:physiology; D003292:Convulsants / Q000494:pharmacology; D004026:Dieldrin / Q000494:pharmacology; D004330:Drosophila / Q000187:drug effects; D000431:Ethanol / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology*; D008658:Inactivation, Metabolic; D007305:Insecticide Resistance; D015640:Ion Channel Gating; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D039821:Monoterpenes; D011817:Rabbits; D051381:Rats; D018079:Receptors, GABA / Q000187:drug effects*; D013729:Terpenes / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D000081008:Bicyclic Monoterpenes; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018118:Chloride Channels; D003292:Convulsants; D018757:GABA Modulators; D039821:Monoterpenes; D018079:Receptors, GABA; D013729:Terpenes; C091518:1-(4-ethynylphenyl)-4-propyl-2,6,7-trioxabicyclo(2.2.2)octane; D000431:Ethanol; D005680:gamma-Aminobutyric Acid; C005790:beta-thujone; D004026:Dieldrin