Mechanism for inhibitory effect of cannabidiol on microsomal testosterone oxidation in male rat liver.
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.
Narimatsu
S
S
Department of Hygienic Chemistry, School of Pharmacy, Hokuriku University, Kanazawa, Japan.
Watanabe
K
K
Yamamoto
I
I
Yoshimura
H
H
D000818:Animals; D001711:Biotransformation; D002185:Cannabidiol / Q000494:pharmacology*; D002186:Cannabinoids / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D066298:In Vitro Techniques; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010084:Oxidation-Reduction; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013739:Testosterone / Q000378:metabolism*
D002186:Cannabinoids; D011725:Pyridines; C013109:metapyrone; D002185:Cannabidiol; D013739:Testosterone; D003577:Cytochrome P-450 Enzyme System; D008797:Metyrapone