| Published Scientific Papers on Thujone |
α-Thujone (the active component of absinthe): γ-Aminobutyric acid type A receptor
modulation and metabolic detoxification
by Karin M. Höld, Nilantha s. Sirisoma, Tomoko Ikeda, Toshio Narahashi and John E. Casida
Published in PNAS, April 2000
modulation and metabolic detoxification
by Karin M. Höld, Nilantha s. Sirisoma, Tomoko Ikeda, Toshio Narahashi and John E. Casida
Published in PNAS, April 2000
Abstract
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 thujone neurotoxicity and identifies its major metabolites and their role in
the poisoning process. Four observations establish that -thujone is a modulator of the 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 -thujone. Third, thujone
is a competitive inhibitor of [3H]ethynylbicycloorthobenzoate binding to mouse brain membranes. Most definitively, GABA-induced peak
currents in rat dorsal root ganglion neurons are suppressed by thujone with complete reversal after washout. Thujone is quickly
metabolized in vitro by mouse liver microsomes with NADPH (cytochrome P450) forming 7-hydroxy--thujone as the major product plus
five minor ones (4-hydroxy--thujone, 4-hydroxy--thujone, two other hydroxythujones, and 7,8-dehydro--thujone), several of which also are
detected in the brain of mice treated i.p. with -thujone. The major 7-hydroxy metabolite attains much higher brain levels than 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, thujone in absinthe and herbal medicines is a rapid-acting and readily detoxified modulator of the GABA-gated chloride
channel.
Introduction
Absinthe was a popular emerald-green liqueur in the 19th and early 20th centuries. It was commonly imbibed by artists and writers
including Vincent van Gogh, Henri de Toulouse-Lautrec, and Charles Baudelaire, often inducing fits and hallucinations and sometimes
contributing to psychoses and suicides (1-5). Absinthe became an epidemic health problem and was banned in many countries early
in the 20th century, but its use continues legally or illicitly even now (6, 7). The toxic properties of absinthe are attributable to wormwood
oil used in making the beverage. Wormwood oil is in itself a prevalent herbal medicine for treating loss of appetite, dyspeptic disorders,
and liver and gallbladder complaints (8, 9).
Thujone generally is considered to be the principal active ingredient of wormwood oil and toxic principle in absinthe (2). The content of
-thujone often exceeds that of -thujone depending on the plant source, but the -diastereomer (Fig. 1) is generally of lower toxicity.
-Thujone also is reported to have antinociceptive activity in mice (10). This monoterpenoid occurs in many plants, including Artemesia
species, sage, and the Thuja tree (4). Extracts of wormwood were used to control gastrointestinal worms with records back to ancient
Egyptian times (4). Artemesia absinthium and wormwood oil have insecticidal properties (11), and -thujone was one of the two most
toxic monoterpenoids tested against western corn rootworm larvae (12). Public mistrust of synthetic pharmaceuticals and pesticides
has led to the increasing popularity of herbal medicines and botanical insecticides even though they have not been subjected to the
same rigorous tests of safety and evaluation of toxicological mechanisms (13-15).
The toxic effects of thujone in mammals are well established but the mode of neurotoxic action is poorly understood. It is porphyrogenic,
possibly thereby contributing to the absinthe-induced illness of Vincent van Gogh (5, 16). Thujone is neurotoxic in rats (17), and
ingestion of wormwood oil containing thujone recently resulted in human poisoning (18). The hypothesis that thujone activates the CB1
cannabinoid receptor, based on the structural similarity of thujone enol with tetrahydrocannabinol (19), was not supported
experimentally (20). The convulsant action led to multiple speculations on mechanisms, one of which was antagonism of the
-aminobutyric acid (GABA) receptor system (20), a proposal that was not explored further. Alpha and beta thujone are reduced in rabbits
from the ketones to the corresponding alcohols (thujol and neothujol) (21) of unknown toxicity but no other metabolites are identified.
The goals of this study are to define the mechanism of neurotoxicity of -thujone and identify its major metabolites and their role in the
poisoning process. Emphasis is placed on the hypothesis that the convulsant action is caused by modulating the GABA-gated chloride
channel.
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 thujone neurotoxicity and identifies its major metabolites and their role in
the poisoning process. Four observations establish that -thujone is a modulator of the 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 -thujone. Third, thujone
is a competitive inhibitor of [3H]ethynylbicycloorthobenzoate binding to mouse brain membranes. Most definitively, GABA-induced peak
currents in rat dorsal root ganglion neurons are suppressed by thujone with complete reversal after washout. Thujone is quickly
metabolized in vitro by mouse liver microsomes with NADPH (cytochrome P450) forming 7-hydroxy--thujone as the major product plus
five minor ones (4-hydroxy--thujone, 4-hydroxy--thujone, two other hydroxythujones, and 7,8-dehydro--thujone), several of which also are
detected in the brain of mice treated i.p. with -thujone. The major 7-hydroxy metabolite attains much higher brain levels than 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, thujone in absinthe and herbal medicines is a rapid-acting and readily detoxified modulator of the GABA-gated chloride
channel.
Introduction
Absinthe was a popular emerald-green liqueur in the 19th and early 20th centuries. It was commonly imbibed by artists and writers
including Vincent van Gogh, Henri de Toulouse-Lautrec, and Charles Baudelaire, often inducing fits and hallucinations and sometimes
contributing to psychoses and suicides (1-5). Absinthe became an epidemic health problem and was banned in many countries early
in the 20th century, but its use continues legally or illicitly even now (6, 7). The toxic properties of absinthe are attributable to wormwood
oil used in making the beverage. Wormwood oil is in itself a prevalent herbal medicine for treating loss of appetite, dyspeptic disorders,
and liver and gallbladder complaints (8, 9).
Thujone generally is considered to be the principal active ingredient of wormwood oil and toxic principle in absinthe (2). The content of
-thujone often exceeds that of -thujone depending on the plant source, but the -diastereomer (Fig. 1) is generally of lower toxicity.
-Thujone also is reported to have antinociceptive activity in mice (10). This monoterpenoid occurs in many plants, including Artemesia
species, sage, and the Thuja tree (4). Extracts of wormwood were used to control gastrointestinal worms with records back to ancient
Egyptian times (4). Artemesia absinthium and wormwood oil have insecticidal properties (11), and -thujone was one of the two most
toxic monoterpenoids tested against western corn rootworm larvae (12). Public mistrust of synthetic pharmaceuticals and pesticides
has led to the increasing popularity of herbal medicines and botanical insecticides even though they have not been subjected to the
same rigorous tests of safety and evaluation of toxicological mechanisms (13-15).
The toxic effects of thujone in mammals are well established but the mode of neurotoxic action is poorly understood. It is porphyrogenic,
possibly thereby contributing to the absinthe-induced illness of Vincent van Gogh (5, 16). Thujone is neurotoxic in rats (17), and
ingestion of wormwood oil containing thujone recently resulted in human poisoning (18). The hypothesis that thujone activates the CB1
cannabinoid receptor, based on the structural similarity of thujone enol with tetrahydrocannabinol (19), was not supported
experimentally (20). The convulsant action led to multiple speculations on mechanisms, one of which was antagonism of the
-aminobutyric acid (GABA) receptor system (20), a proposal that was not explored further. Alpha and beta thujone are reduced in rabbits
from the ketones to the corresponding alcohols (thujol and neothujol) (21) of unknown toxicity but no other metabolites are identified.
The goals of this study are to define the mechanism of neurotoxicity of -thujone and identify its major metabolites and their role in the
poisoning process. Emphasis is placed on the hypothesis that the convulsant action is caused by modulating the GABA-gated chloride
channel.
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