Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2000 Apr 11;97(8):3826-31.
doi: 10.1073/pnas.070042397.

Alpha-thujone (the active component of absinthe): gamma-aminobutyric acid type A receptor modulation and metabolic detoxification

K M Höld  1 , N S Sirisoma, T Ikeda, T Narahashi, J E Casida
Affiliations

Alpha-thujone (the active component of absinthe): gamma-aminobutyric acid type A receptor modulation and metabolic detoxification

K M Höld et al. Proc Natl Acad Sci U S A. .

Abstract

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.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Structures of α-thujone (1S, 4R, 5R-thujone) and its metabolites in the mouse liver microsomal P450 system, the brain of treated mice, and the urine of treated rabbits. The hydroxythujones and dehydro-α-thujone are observed in the mouse liver microsomal P450 system and in brain whereas thujol and neothujol are identified in the rabbit liver cytosolic ketone reductase system and in urine as conjugates. The major metabolite in mouse brain and the P450 system is 7-hydroxy-α-thujone. β-Thujone is the 1S, 4S, 5R diastereomer (structure not shown).
Figure 2
Figure 2
Drosophila of the dieldrin-resistant (Rdl) strain are also resistant to α-thujone. The susceptible (S) strain is Canton S. Concentration is shown on a logarithmic scale and mortality on a probit scale.
Figure 3
Figure 3
α-Thujone and 7-hydroxy-α-thujone inhibit [3H]EBOB binding to mouse brain membranes. (A) IC50 determination for α-thujone and 7-hydroxy-α-thujone (mean ± SEM, n = 4). (B) Scatchard plots as average of duplicate measurements for [3H]EBOB alone (Kd 2.8 nM and Bmax 1,700 fmol/mg protein) and with α-thujone at 5 μM (Kd 4.1 and Bmax 1,700) and 25 μM (Kd 7.2 and Bmax 1,700).
Figure 4
Figure 4
Suppression of GABA-induced peak currents by bath application of α-thujone. Currents were induced by 300 μM GABA (10 msec) pulses. The peak amplitude of current decreased with 30 μM α-thujone and recovered after washing with α-thujone-free solution. (A) Time course of 30 μM α-thujone-induced changes in peak current amplitude. (B) Representative current records. (C) Concentration-response relationship (mean ± SD, n = 4–5).
Figure 5
Figure 5
Absinthe, ethanol, and ethanol containing α-thujone inhibit [3H]EBOB binding to mouse brain membranes. (A) Comparison of an absinthe preparation (based on ethanol content) with ethanol (average of duplicate measurements or mean ± SD, n = 6). (B) Comparison of ethanol with ethanol containing 5 μM α-thujone (average of duplicate measurements).
Figure 6
Figure 6
Representative GC-MS- selected ion monitoring chromatograms for α-thujone and metabolites extracted from the mouse liver microsome-NADPH (P450) system and the brain of α-thujone-treated mice (50 mg/kg, i.p., 10 min after treatment). The major metabolite is 7-hydroxy-α-thujone. Four minor hydroxythujone metabolites are as follows: 1) 4-hydroxy-α; 3) 4-hydroxy-β; 2 and 4) others. Dehydro refers to 7,8-dehydro-α-thujone. Shaded peaks not derived from α-thujone are an endogenous substance (end) and the internal standard (IS). All thujone-derived metabolites fall within the chromatographic region shown.
Figure 7
Figure 7
Brain levels of α-thujone and 7-hydroxy-α-thujone as a function of dose and time in mice treated i.p. with α-thujone. Average of determinations on two mice except for a single determination at 5 min. (A) Dose studies at 30 min after treatment. (B) Time studies at 50 mg/kg.
See this image and copyright information in PMC

Comment in

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Vogt D D, Montagne M. Int J Addict. 1982;17:1015–1029. - PubMed
    1. Arnold W N. J Am Med Assoc. 1988;260:3042–3044. - PubMed
    1. Conrad B., III . Absinthe: History in a Bottle. San Francisco: Chronicle Books; 1988.
    1. Arnold W N. Sci Am. 1989;6:112–117. - PubMed
    1. Arnold W N. Vincent van Gogh: Chemicals, Crises, and Creativity. Boston, MA: Birkhaüser; 1992. pp. 101–137.

Publication types

MeSH terms

LinkOut - more resources