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

α- and β-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 γ-aminobutyric acid (GABA)-gated chloride channel, and identified 7-hydroxy-α-thujone as the major metabolite and 4-hydroxy-α- and -β-thujones and 7,8-dehydro-α-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-α-thujone is the major urinary metabolite of α-thujone. Hydroxylation at the 4...