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.