QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Miyazawa, M. Articles by Shimada, T. Search for Related Content PubMed PubMed Citation Articles by Miyazawa, M. Articles by Shimada, T.

ROLES OF HUMAN CYP2A6 AND 2B6 AND RAT CYP2C11 AND 2B1 IN THE 10-HYDROXYLATION OF (–)-VERBENONE BY LIVER MICROSOMES

Department of Applied Chemistry, Faculty of Science and Engineering, Kinki University, Kowakae, Higashiosaka, Osaka, Japan (M.M., A.S.); and Osaka Prefectual Institute of Public Health, Osaka, Japan (T.S.)

(–)-Verbenone, a monoterpene bicyclic ketone, is a component of the essential oil from rosemary species such as Rosmarinus officinalis L., Verbena triphylla, and Eucalyptus globulus and is used for an herb tea, a spice, and a perfume. In this study, (–)-verbenone was found to be converted to 10-hydroxyverbenone by rat and human liver microsomal cytochrome P450 (P450) enzymes. The product formation was determined by high-performance liquid chromatography with UV detection at 251 nm. There was a good correlation between activities of coumarin 7-hydroxylation and (–)-verbenone 10-hydroxylation catalyzed by liver microsomes of 16 human samples, indicating that CYP2A6 is a principal enzyme in (–)-verbenone 10-hydroxylation in humans. Human recombinant CYP2A6 and CYP2B6 catalyzed (-)verbenone 10-hydroxylation at V_max values of 15 and 21 nmol/min/nmol P450 with apparent K_m values of 16 and 91 µM, respectively. In contrast, rat CYP2A1 and 2A2 did not catalyze (–)-verbenone 10-hydroxylation at all, suggesting that there were species-related differences in the catalytic properties of human and rat CYP2A enzymes in the metabolism of (–)-verbenone. In the rat, recombinant CYP2C11, CYP2B1, and CYP3A2 catalyzed (–)-verbenone 10-hydroxylation with V_max and K_m ratios (ml/min/nmol P450) of 0.73, 0.20, and 0.03, respectively. Male-specific CYP2C11 was a major enzyme in (–)-verbenone 10-hydroxylation by untreated rat livers, and CYP2B1 catalyzed this reaction in liver microsomes of phenobarbital-treated rats. Rat CYP2C12, a female-specific enzyme, did not catalyze (-)verbenone 10-hydroxylation. These results suggest that human CYP2A6 and rat CYP2C11 are the major catalysts in the metabolism of (–)-verbenone by liver microsomes and that there are species-related differences in human and rat CYP2A enzymes and sex-related differences in male and female rats in the metabolism of (–)-verbenone.