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Research ArticleArticle

Oxidation Mechanism of 7-Hydroxy-Δ8-tetrahydrocannabinol and 8-Hydroxy-Δ9-tetrahydrocannabinol to the Corresponding Ketones by CYP3A11

Tamihide Matsunaga, Hiroyuki Tanaka, Shinsuke Higuchi, Kinya Shibayama, Nobuyuki Kishi, Kazuhito Watanabe and Ikuo Yamamoto
Drug Metabolism and Disposition November 2001, 29 (11) 1485-1491;
Tamihide Matsunaga
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Hiroyuki Tanaka
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Shinsuke Higuchi
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Kinya Shibayama
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Nobuyuki Kishi
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Kazuhito Watanabe
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Ikuo Yamamoto
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Abstract

A cDNA isolated from a C57BL/6 mouse liver cDNA library had the identical nucleotide sequence in coding region with the mouse CYP3A11, and the NH2-terminal sequence was also identical to that of cytochrome P450 (P450) MDX-B, a microsomal alcohol oxygenase. The COS-7 cells transfected with the CYP3A11 expression vector formed 7-oxo-Δ8-tetrahydrocannabinol (7-oxo-Δ8-THC) from 7α- and 7β-hydroxy-Δ8-THC. An immunologically related protein with P450 MDX-B was expressed in the COS-7 cell microsomes. The cell microsomes expressed CYP3A11; COS-3A11 catalyzed the oxidation of 7-hydroxy-Δ8-THC and 8-hydroxy-Δ9-THC to 7-oxo-Δ8-THC and 8-oxo-Δ9-THC, respectively, in a reconstituted system. 18O derived from atmospheric oxygen was incorporated into about 30% of the corresponding ketones formed from 7α-hydroxy-Δ8-THC and 8β-hydroxy-Δ9-THC by mouse hepatic microsomes, P450 MDX-B, and COS-3A11, although incorporation of the stable isotope into the oxidized metabolites from 7β-hydroxy-Δ8-THC and 8α-hydroxy-Δ9-THC was negligible. 18O, however, was not incorporated into 7-oxo-Δ8-THC formed from 7α-hydroxy-Δ8-THC by using cumene hydroperoxide instead of NADPH under 18O2. When18O-labeled 7α-hydroxy-Δ8-THC and 8β-hydroxy-Δ9-THC were incubated with above enzymes under air, about 30% of the ketones formed released 18O from a hydroxy group at the 7 and 8 positions in the course of the oxidation. These results suggest that 7α-hydroxy-Δ8-THC and 8β-hydroxy-Δ9-THC may be oxidized to the corresponding ketones by CYP3A11 via a gem-diol pathway. 7β-Hydroxy-Δ8-THC and 8α-hydroxy-Δ9-THC may be also converted to the ketones through a stereoselective dehydration of an enzyme-bound gem-diol rather than through a direct hydrogen extraction as a peroxy form of the enzyme.

Footnotes

  • This work was partially supported by a grant-in-aid for Scientific Research from the Ministry of Education, Science and Culture of Japan, and by the Special Research Fund of Hokuriku University.

  • Abbreviations used are::
    THC
    tetrahydrocannabinol
    MALCO
    microsomal alcohol oxygenase
    P450
    cytochrome P450
    GC/MS
    gas chromatography/mass spectrometry
    PCR
    polymerase chain reaction
    CuOOH
    cumene hydroperoxide
    • Received April 30, 2001.
    • Accepted August 8, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (11)
Drug Metabolism and Disposition
Vol. 29, Issue 11
1 Nov 2001
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Research ArticleArticle

Oxidation Mechanism of 7-Hydroxy-Δ8-tetrahydrocannabinol and 8-Hydroxy-Δ9-tetrahydrocannabinol to the Corresponding Ketones by CYP3A11

Tamihide Matsunaga, Hiroyuki Tanaka, Shinsuke Higuchi, Kinya Shibayama, Nobuyuki Kishi, Kazuhito Watanabe and Ikuo Yamamoto
Drug Metabolism and Disposition November 1, 2001, 29 (11) 1485-1491;

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Research ArticleArticle

Oxidation Mechanism of 7-Hydroxy-Δ8-tetrahydrocannabinol and 8-Hydroxy-Δ9-tetrahydrocannabinol to the Corresponding Ketones by CYP3A11

Tamihide Matsunaga, Hiroyuki Tanaka, Shinsuke Higuchi, Kinya Shibayama, Nobuyuki Kishi, Kazuhito Watanabe and Ikuo Yamamoto
Drug Metabolism and Disposition November 1, 2001, 29 (11) 1485-1491;
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