title: Stereoselective metabolism of the monoterpene carvone by rat and human liver microsomes.
abstract: The large amounts of carvone enantiomers consumed as food additives and in dental formulations justifies the evaluation of their biotransformation pathway. The in-vitro metabolism of R-(-)- and S-(+)-carvone was studied in rat and human liver microsomes using chiral gas chromatography. Stereoselective biotransformation was observed when each enantiomer was incubated separately with liver microsomes. 4R, 6S-(-)-Carveol was NADPH-dependently formed from R-(-)-carvone, whereas 4S, 6S-(+)-carveol was produced from S-(+)-carvone. Metabolite formation followed Michaelis-Menten kinetics exhibiting a significant lower apparent Km (Michaelis-Menten Constant) for 4R, 6S-(-)-carveol compared with 4S, 6S-(+)-carveol in rat and human liver microsomes (28.4+/-10.6 microM and 69.4+/-10.3 microM vs 33.6+/-8-55 microM and 98.3+/-22.4 microM). The maximal formation rate (Vmax) determined in the same microsomal preparations yielded 30.2+/-5.0 and 32.3+/-3.9 pmol (mg protein)(-1) min(-1) in rat liver and 55.3+/-5.7 and 65.2+/-4.3 pmol (mg protein)(-1) min(-1) in human liver microsomes. Phase II conjugation of the carveol isomers by rat and human liver microsomes in the presence of UDPGA (uridine S'-diphosphogluaronic acid) only revealed glucuronidation of 4R, 6S-(-)-carveol. Vmax for glucuronide formation was more than 4-fold higher in the rat liver compared with human liver preparations (185.9+/-34.5 and 42.6+/-7.1 pmol (mg protein)(-1) min(-1), respectively). Km values, however, showed no species-related difference (13.9+/-4.1 microM and 10.2+/-2.2 microM). This study demonstrated stereoselectivity in phase-I and phase-II metabolism for R-(-)- and S-(+)-carvone and might be predictive for carvone biotransformation in man.
authors.affiliation: Institute of Pharmaceutical Chemistry, University of Vienna, Austria. wjaeger@speedy.pch.univie.ac.at
authors.forename: W
authors.initials: W
authors.lastname: Jäger
authors.forename: M
authors.initials: M
authors.lastname: Mayer
authors.forename: P
authors.initials: P
authors.lastname: Platzer
authors.forename: G
authors.initials: G
authors.lastname: Reznicek
authors.forename: H
authors.initials: H
authors.lastname: Dietrich
authors.forename: G
authors.initials: G
authors.lastname: Buchbauer
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000493:pharmacokinetics*; D001711:Biotransformation; D000081005:Cyclohexane Monoterpenes; D003764:Dental Materials / Q000737:chemistry; D005503:Food Additives / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D039821:Monoterpenes; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013729:Terpenes / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000081005:Cyclohexane Monoterpenes; D003764:Dental Materials; D005503:Food Additives; D039821:Monoterpenes; D013729:Terpenes; C006923:carvone