(-)-3-Isothujone, a small nonnitrogenous molecule with antinociceptive activity in mice

Rice, Kenner C.; Wilson, Raymond S.

doi:10.1021/jm00230a015

Cited by 48 publications

(29 citation statements)

References 8 publications

(28 reference statements)

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“…␤-Thujone is less toxic than ␣-thujone to mice (10) and Drosophila and in addition is 2.3-fold less potent in the [ 3 H]E-BOB assay (this investigation). Ethanol also enhances neuronal GABA A receptor function (30) and therefore might suppress the blocking action of ␣-thujone in absinthe.…”

Section: Discussionmentioning

confidence: 72%

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α-Thujone (the active component of absinthe): γ-Aminobutyric acid type A receptor modulation and metabolic detoxification

Höld

Sirisoma

Ikeda

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

321

172

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␣-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 [ 3 H]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.

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Section: Discussionmentioning

confidence: 72%

“…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).…”

mentioning

confidence: 99%

α-Thujone (the active component of absinthe): γ-Aminobutyric acid type A receptor modulation and metabolic detoxification

Höld

Sirisoma

Ikeda

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

321

172

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“…extract decreased total motility, locomotor activity and rearing behaviour and showed sedative, anxiolitic and antidepressant effects in rats (Mora et al 2005). Individually, the compound α-Thujone has been found to have antinociceptive activity (Rice and Wilson 1976) and convulsionant activity in mice (Hold et al 2000) and neurotoxicity in rats (Millet et al 1981). In addition, it has been classified as a neurotoxic insecticide (Hold et al 2001; and pesticide (Duke 2004).…”

Section: Introductionmentioning

confidence: 99%

Effects of the essential oils of Lippia turbinata and Lippia polystachya (Verbenaceae) on the temporal pattern of locomotion of the mosquito Culex quinquefasciatus (Diptera: Culicidae) larvae

et al. 2008

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The essential oils (EO) of Lippia turbinata (TUR) and Lippia polystachya (POL) have shown lethal effects against mosquito larvae. The present work evaluated whether these EO at doses ranging from sublethal to lethal (20, 40 and 80 ppm) modify the temporal pattern of locomotion of Culex quinquefasciatus larvae. Larvae were individually placed in glass boxes, and their activity recorded at 0.3 s intervals during 40 min. Individuals treated with doses >40 ppm of either EO significantly decreased their ambulation speed and the percentage of total time ambulating compared to controls. TUR 80 ppm decreased their ambulation even sooner than POL 80 ppm, when compared to their respective controls. These findings are consistent with the neurotoxic effect against insects attributed to alpha-Thujone, a main component of both EO. A detrended fluctuation fractal analysis evaluating the complexity and organisation of the temporal pattern of locomotion showed fractal patterns in all animals. Both sublethal and lethal doses of TUR and POL increased the complexity of ambulation. Interestingly, for POL 20 ppm, an increase in complexity was observed, while no changes in general activity were detected, suggesting that fractal analysis may be more sensitive to detect behavioural changes than general activity evaluation.

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“…This explains their convulsant action in mammals and probably their insecticidal activity (7)(8)(9). RT is more toxic than T to mice (10) and more potent at the GABA-gated chloride channel (7). RT also has porphyrogenic properties and is potentially hazardous to patients with acute hepatic porphyrias (11).…”

Section: Introductionmentioning

confidence: 99%

Detoxification of α- and β-Thujones (the Active Ingredients of Absinthe): Site Specificity and Species Differences in Cytochrome P450 Oxidation in Vitro and in Vivo

Höld

Sirisoma

Casida

2001

Chem. Res. Toxicol.

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Alpha- and beta-Thujones are active ingredients in the liqueur absinthe and in herbal medicines and seasonings for food and drinks. Our earlier study established that they are convulsants and have insecticidal activity, acting as noncompetitive blockers of the gamma-aminobutyric acid (GABA)-gated chloride channel, and identified 7-hydroxy-alpha-thujone as the major metabolite and 4-hydroxy-alpha- and -beta-thujones and 7,8-dehydro-alpha-thujone as minor metabolites in the mouse liver microsome-NADPH system. We report here unexpected site specificity and species differences in the metabolism of the thujone diastereomers in mouse, rat, and human liver microsomes and human recombinant P450 (P450 3A4), in orally treated mice and rats, and in Drosophila melanogaster. Major differences are apparent on comparing in vitro microsome-NADPH systems and in vivo urinary metabolites. Hydroxylation at the 2-position is observed only in mice where conjugated 2R-hydroxy-alpha-thujone is the major urinary metabolite of alpha-thujone. Hydroxylation at the 4-position gives one or both of 4-hydroxy-alpha- and -beta-thujones depending on the diastereomer and species studied with conjugated 4-hydroxy-alpha-thujone as the major urinary metabolite of alpha- and beta-thujones in rats. Hydroxylation at the 7-position of alpha- and beta-thujones is always a major pathway, but the conjugated urinary metabolite is minor except with beta-thujone in the mouse. Site specificity in glucuronidation favors excretion of 2R-hydroxy- and 4-hydroxy-alpha-thujone glucuronides rather than those of three other hydroxythujones. Two dehydro metabolites are observed from both alpha- and beta-thujones, the 7,8 in the P450 systems and the 4,10 in urine. Two types of evidence establish that P450-dependent oxidations of alpha- and beta-thujones are detoxification reactions: three P450 inhibitors block the metabolism of alpha- and beta-thujones and strongly synergize their toxicity in Drosophila; six metabolites assayed are less potent than alpha- and beta-thujones as inhibitors of [(3)H]ethynylbicycloorthobenzoate binding to the GABA(A) receptor in mouse brain membranes and as toxicants to Drosophila.

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(-)-3-Isothujone, a small nonnitrogenous molecule with antinociceptive activity in mice

Cited by 48 publications

References 8 publications

α-Thujone (the active component of absinthe): γ-Aminobutyric acid type A receptor modulation and metabolic detoxification

α-Thujone (the active component of absinthe): γ-Aminobutyric acid type A receptor modulation and metabolic detoxification

Effects of the essential oils of Lippia turbinata and Lippia polystachya (Verbenaceae) on the temporal pattern of locomotion of the mosquito Culex quinquefasciatus (Diptera: Culicidae) larvae

Detoxification of α- and β-Thujones (the Active Ingredients of Absinthe): Site Specificity and Species Differences in Cytochrome P450 Oxidation in Vitro and in Vivo

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