Study on the cytochrome P450-mediated oxidative metabolism of the terpene alcohol linalool: indication of biological epoxidation.
The cytochrome P450-mediated oxidative metabolism of the terpene alcohol linalool was studied in vitro by enzymatic assays using recombinant human cytochrome P450 enzymes. Three different enzymatic products of allylic hydroxylation and epoxidation were identified by gas chromatography-mass spectrometry. Identified enzymatic products were 8-hydroxylinalool ((R/S)-3,7-dimethyl-1,6-octadiene-3,8-diol) and the cyclic ethers pyranoid-linalool oxide ((R/S)-2,2,6-trimethyl-6-vinyltetrahydro-2H-pyran-3-ol) and furanoid-linalool oxide (R/S)-2-(1,1-dimethylethyl)-5-methyl-5-vinyltetrahydrofuran. The cyclic ethers result most likely from the epoxidation of the 6,7-carbon double carbon bond of (R/S)-linalool, followed by the intramolecular rearrangement of the 6,7-epoxy-linalool. Allylic-hydroxylation of the 8-methyl group of linalool was catalyzed by CYP2C19 and CYP2D6 while the enzymatic epoxidation of linalool was only observed with CYP2D6. The results indicate that the electrophilic oxidation products of linalool such as 6,7-epoxy-linalool which may cause sensitization and irritational skin reactions are not only produced by auto-oxidation reactions in the presence of air-oxygen as published in the past, but also by P450-mediated oxidative biological transformation.
Meesters
R J W
RJ
Institute of Hygiene and Environmental Medicine, RWTH Aachen University, Germany.
Duisken
M
M
Hollender
J
J
D000080462:Acyclic Monoterpenes; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D004852:Epoxy Compounds / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D039821:Monoterpenes / Q000737:chemistry / Q000378:metabolism*; D010084:Oxidation-Reduction; D011994:Recombinant Proteins / Q000378:metabolism
D000080462:Acyclic Monoterpenes; D004852:Epoxy Compounds; D039821:Monoterpenes; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System; C018584:linalool