Mechanism for inhibitory effect of cannabidiol on microsomal testosterone oxidation in male rat liver

Drug Metab Dispos. 1988 Nov-Dec;16(6):880-9.

Abstract

Effects of four cannabinoids [cannabidiol (CBD), delta 8-tetrahydrocannabinol, delta 9-tetrahydrocannabinol, and cannabinol] on hepatic microsomal oxidation of testosterone (17 beta-hydroxy-androst-4-ene-3-one) were examined in adult male rats. Only CBD (30 microM) competitively inhibited 2 alpha-hydroxy-testosterone (2 alpha-OH-T) and 16 alpha-OH-T formation by hepatic microsomes but did not affect androstenedione (androst-4-ene-3,17-dione) and 7 alpha-OH-T formation. Kinetic analyses demonstrated that the inhibitory profile of CBD for testosterone oxidation was different from those of SKF 525-A, which caused competitive inhibition for 2 alpha- and 16 alpha-hydroxylations and noncompetitive inhibition for 6 alpha-hydroxylation, and of metyrapone, which inhibited only 6 beta-hydroxylation competitively. CBD also suppressed formation of 2 alpha-OH-T, 16 alpha-OH-T, and androstenedione from testosterone, catalyzed by a reconstituted system containing hepatic cytochrome P-450 purified from phenobarbital-treated rats. Pretreatment of the rat with CBD (10 mg/kg, ip, once a day for 3 days) decreased testosterone oxidation at the 2 alpha-, 16 alpha-, and 17-positions and increased 7 alpha-OH-T formation, while total cytochrome P-450 content was decreased. These results suggest that CBD suppresses hepatic testosterone oxidation at the 2 alpha-, 16 alpha-, and 17-positions through selective inhibition of the male-specific cytochrome P-450 in the adult male rat.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biotransformation
  • Cannabidiol / pharmacology*
  • Cannabinoids / pharmacology*
  • Cytochrome P-450 Enzyme System / metabolism
  • Electrophoresis, Polyacrylamide Gel
  • In Vitro Techniques
  • Male
  • Metyrapone / pharmacology
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • Microsomes, Liver / metabolism*
  • Oxidation-Reduction
  • Pyridines / pharmacology
  • Rats
  • Rats, Inbred Strains
  • Testosterone / metabolism*

Substances

  • Cannabinoids
  • Pyridines
  • metapyrone
  • Cannabidiol
  • Testosterone
  • Cytochrome P-450 Enzyme System
  • Metyrapone