Enzymatic oxidation of 7-hydroxylated Δ8-tetrahydrocannabinol to 7-oxo-Δ8-tetrahydrocannabinol by hepatic microsomes of the guinea pig

S. Narimatsu, K. Matsubara, T. Shimonishi, K. Watanabe, I. Yamamoto, H. Yoshimura

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Abstract

Hepatic microsomes of the guinea pig converted Δ8-tetrahydrocannabinol (Δ8-THC) to various oxidized metabolites, including 7α-hydorxy-Δ8-THC (7α-OH-Δ8-THC), 7β-OH-Δ8-THC, and 7-oxo-Δ8-THC. The enzyme which mediates biotransformation of 7-OH-Δ8-THCs to 7-oxo-Δ8-THC was characterized in the present study. The oxidative activity was mainly located in microsomes. The microsomal reaction required NADPH and oxygen and showed an optimal pH around 7.5. The reaction was inhibited by β-diethylaminoethyl diphenylpropylacetate (SKF 525-A), an inhibitor of cytochrome P-450, but not by pyrazole, a specific inhibitor of alcohol dehydrogenase. However, 7-oxo-Δ8-THC formation was not affected by carbon monoxide or by pretreatment of animals with cobaltous chloride (40 mg/kg, ip, once a day for 3 days). Atmospheric oxygen was incorporated into 7-oxo-Δ8-THC formed from 7α-OH-Δ8-THC, but not into that from 7β-OH-Δ8-THC. Further, 7-oxo-Δ8-THC formed from 7α-18OH-Δ8-THC released about half of 18O at the 7-position, whereas the 7-oxo metabolite from 7β-18OH-Δ8-THC lost little of the isotope at the 7β-position during the oxidative reaction. From these results, it is likely that hepatic microsomal monooxygenase (probably cytochrome P-450) plays a main role in the oxidation. In addition, mechanisms for 7-oxo-Δ8-THC formation from 7α-OH-Δ8-THC or 7β-OH-Δ8-THC are different.

Original languageEnglish
Pages (from-to)156-161
Number of pages6
JournalDrug Metabolism and Disposition
Volume16
Issue number1
Publication statusPublished - Jan 1 1988

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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    Narimatsu, S., Matsubara, K., Shimonishi, T., Watanabe, K., Yamamoto, I., & Yoshimura, H. (1988). Enzymatic oxidation of 7-hydroxylated Δ8-tetrahydrocannabinol to 7-oxo-Δ8-tetrahydrocannabinol by hepatic microsomes of the guinea pig. Drug Metabolism and Disposition, 16(1), 156-161.