Metabolism and mode of action of cis- and trans-3-pinanones (the active ingredients of hyssop oil).
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 gamma-aminobutyric acid type A (GABAA) receptor antagonists based on inhibition of 4'-ethynyl-4-n-[2,3-(3)H(2)]propylbicycloorthobenzoate ([(3)H]EBOB) binding in mouse brain membranes (IC(50) of 35-64 microM) and supported by tonic/clonic convulsions in mouse (i.p. LD(50) 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 [(3)H]EBOB binding.
Höld
K M
KM
Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, 114 Wellman Hall, University of California, Berkeley, CA 94720-3112, USA.
Sirisoma
N S
NS
Sparks
S E
SE
Casida
J E
JE
D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000037:antagonists & inhibitors / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D007306:Insecticides / Q000037:antagonists & inhibitors / Q000378:metabolism; D007928:Lethal Dose 50; D019684:Magnoliopsida / Q000737:chemistry* / Q000378:metabolism; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D015394:Molecular Structure; D010936:Plant Extracts / Q000378:metabolism / Q000633:toxicity / Q000652:urine; D010938:Plant Oils / Q000378:metabolism* / Q000633:toxicity; D010946:Plants, Medicinal / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D013729:Terpenes / Q000378:metabolism* / Q000633:toxicity / Q000652:urine
D019086:Bridged Bicyclo Compounds, Heterocyclic; D007306:Insecticides; D010936:Plant Extracts; D010938:Plant Oils; D013729:Terpenes; C091518:1-(4-ethynylphenyl)-4-propyl-2,6,7-trioxabicyclo(2.2.2)octane; D003577:Cytochrome P-450 Enzyme System