Mol Pharmacol. 1990 Sep;38(3):319-26.  

Selective inactivation of mouse liver cytochrome P-450IIIA by cannabidiol.

Bornheim LM, Correia MA.

Department of Pharmacology, University of California, San Francisco 94143.

Cannabidiol (CBD) inhibits hepatic drug metabolism in mice, particularly those
activities known to be catalyzed by the cytochrome P-450IIIA (P-450IIIA)
subfamily. CBD treatment (120 mg/kg) inhibited more than 75% of hepatic 6
beta-testosterone hydroxylase and erythromycin N-demethylase activities
(functional markers of P-450IIIA) after 2 hr. An isozyme of the P-450IIIA
subfamily (Mr 49,960) was purified to apparent homogeneity from hepatic
microsomes of untreated mice and was found to catalyze testosterone
hydroxylation at the 2 beta-, 6 beta-, and 15 beta-positions exclusively.
Incubation of this isozyme with CBD in a reconstituted system resulted in a
time- and concentration-dependent inactivation, with almost complete loss of
P-450 chromophore and corresponding increase in P-420 content. NH2-terminal
sequence analysis of the isozyme revealed an 86% similarity to the corresponding
sequence of rat P-450IIIA2, a constitutive P-450 isozyme in the male rat liver.
Pretreatment of mice with dexamethasone markedly (6-fold) increased the
steroid-inducible P-450IIIA-dependent activities 6 beta-testosterone
hydroxylation and erythromycin N-demethylation. CBD treatment of
dexamethasone-pretreated animals failed to inhibit these activities, indicating
that the steroid-inducible P-450IIIA was refractory to CBD-mediated
inactivation. 3-Methylcholanthrene-inducible P-450IA and phenobarbital-inducible
P-450IIB also appear to be refractory to CBD-mediated inactivation. On the other
hand, erythromycin N-demethylase activity increased 4-fold after phenobarbital
pretreatment and, as in untreated animals, was comparably inhibited by CBD,
demonstrating its susceptibility to this drug. Thus, CBD appears to inactivate
the P-450IIIA isozymes that are constitutively present in hepatic microsomes of
untreated mice and/or inducible by phenobarbital pretreatment but not those that
are steroid inducible.

PMID: 2402224 [PubMed - indexed for MEDLINE]