Inhibition of hepatic microsomal cytochrome P450 by cannabidiol in adult male rats.
The mechanism of inhibitory effect of cannabidiol (CBD) on the hepatic drug-metabolizing enzyme system was studied in adult male rats in vivo. Time course studies revealed that microsomal d-benzphetamine N-demethylation and testosterone 2 alpha-, 16 alpha- and 17-oxidation were markedly suppressed 6 to 48 h after the single administration of CBD (10 mg/kg, intraperitoneally). Decreases in activities of aniline hydroxylation and p-nitroanisole O-demethylation and in content of total cytochrome P450 were intermittent and moderate. On the other hand, no change was observed in reduced nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome c reductase activity or cytochrome b5 content in the hepatic microsomes of the CBD-treated rats. Western blotting analysis showed a marked decrease in the male-specific cytochrome P450 UT-2 in the hepatic microsomes, especially 24 to 48 h after pretreatment with CBD. It is possible that CBD given 6 to 12 h before the sacrifice might interact with cytochrome P450 as a substrate, resulting in inhibition of the drug-metabolizing enzyme activities in the earlier stages. In the later stages from 24 to 48 h after CBD treatment, the reduction in content of the male-specific cytochrome P450 UT-2 may play a major role in the inhibitory effect of CBD on the hepatic drug-metabolizing enzyme system in the adult male rat in vivo.
Narimatsu
S
S
Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan.
Watanabe
K
K
Matsunaga
T
T
Yamamoto
I
I
Imaoka
S
S
Funae
Y
Y
Yoshimura
H
H
D000818:Animals; D002185:Cannabidiol / Q000494:pharmacology*; D002186:Cannabinoids / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D011919:Rats, Inbred Strains
D002186:Cannabinoids; D065607:Cytochrome P-450 Enzyme Inhibitors; D002185:Cannabidiol