Oxidation mechanism of 7-hydroxy-δ 8-tetrahydrocannabinol and 8-hydroxy-δ9-tetrahydrocannabinol to the corresponding ketones by CYP3A11

Tamihide Matsunaga, Hiroyuki Tanaka, Shinsuke Higuchi, Kinya Shibayama, Nobuyuki Kishi, Kazuhito Watanabe, 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 NH 2-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-Δ 8-tetrahydrocannabinol (7-oxo-Δ 8-THC) from 7α- and 7β-hydro-Δ 8-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-Δ 8-THC and 8-hydroxy-Δ 9-THC to 7-oxo-Δ 8-THC and 8-oxo-Δ 9-THC, respectively, in a reconstituted system. 18O derived from atmospheric oxygen was incorporated into about 30% of the corresponding ketones formed from 7α-hydroxy-Δ 8-THC and 8β-hydroxy-Δ 9-THC by mouse hepatic microsomes, P450 MDX-B, and COS-3A11, although incorporation of the stable isotope into the oxidized metabolites from 7β-hydroxy-Δ 8-THC and 8α-hydroxy-Δ 9 -THC was negligible. 18O, however, was not incorporated into 7-oxo-Δ 8 -THC formed from 7α-hydroxy-Δ 8THC by using cumene hydroperoxide instead of NADPH under 18O 2. When 18O-labeled 7α-hydroxy-Δ 8 -THC and 8β-hydroxy-Δ 9-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-Δ 8 -THC and 8β-hydroxy-Δ 9-THC may be oxidized to the corresponding ketones by CYP3A11 via a gem-diol pathway. 7β-Hydroxy-Δ 8-THC and 8α-hydroxy-Δ 9-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.

Original languageEnglish
Pages (from-to)1485-1491
Number of pages7
JournalDrug Metabolism and Disposition
Volume29
Issue number11
Publication statusPublished - 2001
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science

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    Matsunaga, T., Tanaka, H., Higuchi, S., Shibayama, K., Kishi, N., Watanabe, K., & Yamamoto, I. (2001). Oxidation mechanism of 7-hydroxy-δ 8-tetrahydrocannabinol and 8-hydroxy-δ9-tetrahydrocannabinol to the corresponding ketones by CYP3A11. Drug Metabolism and Disposition, 29(11), 1485-1491.