Cytochrome P-450 isozymes in metabolic activation of Δ9-tetrahydrocannabinol by rat liver microsomes

S. Narimatsu, K. Watanabe, T. Matsunaga, I. Yamamoto, S. Imaoka, Y. Funae, H. Yoshimura

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Abstract

Δ9-Tetrahydrocannabinol (THC) was incubated with a reconstituted system consisting of dilauroylphosphatidylcholine, NADPH-cytochrome c reductase, cytochrome b5, and cytochrome P-450 (P-450) isozyme UT-2, UT-4, or UT-5, which was purified from liver microsomes of adult male rats. It was biotransformed by UT-2 to 11-OH-Δ9-THC and 3'-OH-Δ9-THC, and by UT-4 to 8β-OH-Δ9-THC and 11-OH-Δ9-THC. UT-5, however, showed only a little activity for 11-OH-Δ9-THC formation. Activity of the isozyme UT-2 for 11-OH-Δ9-THC formation from Δ9-THC was calculated to be 4.07 nmol/min/nmol P-450, while those of UT-2 for the formations of 16α-OH-testosterone (16α-OH-T), 2α-OH-T, and androstenedione from testosterone were 14.7, 6.6, and 2.2 nmol/min/nmol P-450, respectively. Anti-P-450 UT-2-IgG fraction obtained from rabbit serum dose-dependently suppressed formations of 16α-OH-T, 2α-OH-T, and androstenedione from testosterone with liver microsomes of adult male rats. The antibody, in the amount that inhibited above 90% of 16α-OH-T and 2α-OH-T formations from testosterone, also reduced 80% of the microsomal formations of 11-OH-Δ9-THC and 3'-OH-Δ9-THC from Δ9-THC, as compared with control experiments using preimmune IgG fraction. These results indicate that UT-2, the major male-specific P-450 isozyme catalyzing testosterone oxidation, plays the major role in the formation of active metabolites of Δ9-THC, such as 11-OH-Δ9-THC and 3'-OH-Δ9-THC, in adult male rats.

Original languageEnglish
Pages (from-to)943-948
Number of pages6
JournalDrug Metabolism and Disposition
Volume18
Issue number6
Publication statusPublished - Dec 1 1990

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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    Narimatsu, S., Watanabe, K., Matsunaga, T., Yamamoto, I., Imaoka, S., Funae, Y., & Yoshimura, H. (1990). Cytochrome P-450 isozymes in metabolic activation of Δ9-tetrahydrocannabinol by rat liver microsomes. Drug Metabolism and Disposition, 18(6), 943-948.