Stereoselective metabolism of the monoterpene carvone by rat and human liver microsomes.
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.
Jäger
W
W
Institute of Pharmaceutical Chemistry, University of Vienna, Austria. wjaeger@speedy.pch.univie.ac.at
Mayer
M
M
Platzer
P
P
Reznicek
G
G
Dietrich
H
H
Buchbauer
G
G
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*
D000972:Antineoplastic Agents, Phytogenic; D000081005:Cyclohexane Monoterpenes; D003764:Dental Materials; D005503:Food Additives; D039821:Monoterpenes; D013729:Terpenes; C006923:carvone