Volume 65, Issue 1, February 2013, Pages 100–107
- a Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, FIN-90014 Oulu, Finland
- b European Medicines Agency, Committee of Herbal Medicinal Products, London E14 4HB, United Kingdom
- c Centre For Arctic Medicine, Thule Institute, University of Oulu, FIN-90014 Oulu, Finland
- d Federal Institute for Drugs and Medical Devices (BfArM), Complementary and Alternative Medicines and Traditional Medicines, Kurt-Georg-Kiesinger-Allee 3, D-53175 Bonn, Germany
- Received 15 June 2012, Available online 27 November 2012
Abstract
Thujone,
a major component of the notoriously famous absinthe drink, is
neurotoxic, although the current view rather downgrades its risk to
humans. In animal studies, thujone inhibits the gamma-aminobutyric acid A
(GABAA) receptor causing excitation and convulsions in a
dose-dependent manner, although there are uncertainties about the doses
required in humans. Toxicity of thujone has been extensively studied.
Neurotoxicity is the principal toxic outcome in acute and chronic
studies. There is some equivocal evidence of carcinogenicity in rats.
Metabolism of thujone has been elucidated both in vitro and in vivo in
several species and in vitro in human liver preparations. CYP2A6 is the
principal metabolic enzyme, followed by CYP3A4 and, to a lesser extent,
CYP2B6. CYP-associated metabolism may give rise to some potential
pharmacogenetic and metabolic interaction consequences. Although the
data base for determining exposure limits is of variable usefulness, the
best estimates for allowable daily intakes via herbal preparations and
diet are of the order of 3–7 mg/day. There are still important gaps in
the knowledge required to assess thujone toxicity, the most important
ones being human dose-concentration-effect relationships including the
elucidation of bioavailability, and the actual toxicological
consequences of potential pharmacogenetic variations and environmental
factors.
Highlights
► Thujone (e.g. in absinthe) has a long-term reputation as a neurotoxicant. ► α-Thujone is rapidly acting modulator of the GABAA-receptor.
► Thujone occurs widely in essential oils of medicinal and botanical
plants. ► Analytical techniques are available to detect α- and β-thujone
in various matrices. ► Regulatory status needs re-assessment based on
focussed investigations.
Keywords
- Thujone;
- Risk assessment;
- Toxicity;
- Metabolism;
- Pharmacokinetics
Abbreviations
- ADI, acceptable daily intake;
- BMDL, benchmark dose (lower confidence limit);
- CNS, central nerve system;
- CYP, cytochrome P450;
- EMA, European Medicines Agency;
- GABAA, gamma-aminobutyric acid type A receptor;
- GC–FID, gas chromatography–flame ionization detector;
- GC–MS, gas chromatography–mass spectrometry;
- HMPC, Committee of Herbal Medicinal Products;
- HS-SPME, head-space solid phase micro extraction;
- LC/MS, liquid chromatography–mass spectrometry;
- LC–TOF, liquid chromatography–time of flight;
- NLM, National Library of Medicine;
- NOEL, no-observed-effect-level;
- NTP, National Toxicology Program;
- SCF, Scientific Committee on Food;
- TDI, tolerable daily intake;
- TMDI, theoretical maximum daily intake
Copyright © 2012 Elsevier Inc. All rights reserved.
