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Xenobiotica
the fate of foreign compounds in biological systems
Volume 32, 2002 - Issue 4
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Research Article

Metabolism and mode of action of cis- and trans-3-pinanones (the active ingredients of hyssop oil)

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Pages 251-265 | Published online: 22 Sep 2008
 

Abstract

1. Hyssop oil is an important food additive and herbal medicine and the principal active ingredients are (-)-cis- and (-)-trans-3-pinanones. No information is available on their metabolism or specific mode of action. 2. The metabolites of cis- and trans-3-pinanones were examined from mouse and human liver microsomes and human recombinant P4503A4 with NADPH and on administration to mouse by gas chromatography/chemical ionization mass spectrometry comparison with standards from synthesis. 3. The major metabolite of cis-3-pinanone in each P450 system and in brain of the i.p.-treated mouse in quantitative studies was 2-hydroxy-cis-3-pinanone, and two minor metabolites were hydroxypinanones other than 2-hydroxy-trans-3-pinanone and 4S-hydroxy-cis-3-pinanone. The urine from oral cis-3-pinanone treatment examined on a qualitative basis contained conjugates of metabolites observed in the microsomal systems plus 2,10-dehydro-3-pinanone. 4. Trans-3-pinanone was metabolized more slowly than the cis -isomer in each system to give hydroxy derivatives different than those derived from cis-3-pinanone. 5. Cis- and trans-3-pinanones and hyssop oil act as γ-aminobutyric acid type A (GABAA) receptor antagonists based on inhibition of 4'-ethynyl-4-n-[2,3-3H2]propylbicycloorthobenzoate ([3H]EBOB) binding in mouse brain membranes (IC50 of 35-64 µM) and supported by tonic/clonic convulsions in mouse (i.p. LD50 175 to >250 mg kg−1) alleviated by diazepam. The cis-3-pinanone metabolites 2-hydroxy-cis-3-pinanone and 2,10-dehydro-3-pinanone exhibit reduced toxicity and potency for inhibition of [3H]EBOB binding.

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