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Research ArticleArticle

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

Mitsuo Miyazawa, Atsushi Sugie and Tsutomu Shimada
Drug Metabolism and Disposition August 2003, 31 (8) 1049-1053; DOI: https://doi.org/10.1124/dmd.31.8.1049
Mitsuo Miyazawa
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Atsushi Sugie
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Tsutomu Shimada
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Abstract

(–)-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 Vmax values of 15 and 21 nmol/min/nmol P450 with apparent Km 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 Vmax and Km 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.

Footnotes

  • ↵1 Abbreviations used are: P450, cytochrome P450; HPLC, high-performance liquid chromotography; PB, phenobarbital; thioTEPA, triethylenethiophosphoramide.

  • This work was supported in part by grants from the Ministry of Education, Science, and Culture of Japan, and the Ministry of Health and Welfare of Japan.

    • Received February 4, 2003.
    • Accepted April 25, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 31 (8)
Drug Metabolism and Disposition
Vol. 31, Issue 8
1 Aug 2003
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Research ArticleArticle

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

Mitsuo Miyazawa, Atsushi Sugie and Tsutomu Shimada
Drug Metabolism and Disposition August 1, 2003, 31 (8) 1049-1053; DOI: https://doi.org/10.1124/dmd.31.8.1049

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Research ArticleArticle

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

Mitsuo Miyazawa, Atsushi Sugie and Tsutomu Shimada
Drug Metabolism and Disposition August 1, 2003, 31 (8) 1049-1053; DOI: https://doi.org/10.1124/dmd.31.8.1049
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