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.

Sedative effects of the jasmine tea odor and (R)-(−)-linalool, one of its major odor components, on autonomic nerve activity and mood states

“…First, we investigated the possibility of sedative effects of the odor of jasmine tea at low intensity in comparison with the odor of lavender because this has been shown pharmacologically to have sedative effects in animals and humans (Buchbauer et al 1991;Hardy et al 1995;Lis-Balchin and Hart 1997a) and it includes a component, (R)-())-linalool, also found in jasmine tea (Ito et al 2002). Second, we investigated whether these effects were caused directly by (R)-())-linalool, and whether its optical isomer (S)-(+)-linalool has the same effects because differing pharmacological effects have been reported for the optical isomers of volatile components (Jager et al 2000(Jager et al , 2001Laska et al 1999).…”

Metabolism of (+)- and (−)-Limonenes to Respective Carveols and Perillyl Alcohols by CYP2C9 and CYP2C19 in Human Liver Microsomes

“…Cytochrome P450 (P450 1 ) enzymes in liver microsomes of these animal species have been shown to oxidize limonene to several oxidation products such as 1,2-and 8,9-epoxides, carveol (a product by 6-hydroxylation), perillyl alcohol (a product by 7-hydroxylation) (Watabe et al, 1980(Watabe et al, , 1981Jager et al, 1999). Recently we reported that limonene enantiomers are oxidized to carveols and perillyl alcohols by CYP2C11 in liver microsomes of untreated rats and by CYP2B1 in those of phenobarbital-treated rats (Miyazawa et al, 2002).…”

Effects of dietary supplementation with sage (Salvia officinalis L.) essential oil on antioxidant status and duodenal wall integrity of laying strain growers

“…In general, metabolic biotransformation of EO compounds occurs in two phases and the final products are glucuronide and sulfate conjugates (Jager 2000). Although the liver is considered the most important organ for biotransformation, Raoof et al (1996) and Shipkova et al (2001) in their studies demonstrated more effective glucuronidation of phenolic compounds in kidney than in liver or intestinal microsomes.…”