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Abstract
Cannabidiol (CBD) has been shown to inhibit mouse hepatic mixed-function oxidations
of several drugs after acute treatment, whereas repetitive treatment resulted in the
restoration of drug-metabolizing capabilities. We have found that acute CBD treatment
modestly decreased cytochrome P-450 content but markedly decreased hexobarbital hydroxylase,
erythromycin N-demethylase, and 6 beta-testosterone hydroxylase activities. Repetitive
CBD treatment, on the other hand, resulted in the restoration of cytochrome P-450
content as well as hexobarbital hydroxylase and erythromycin N-demethylase activities.
However, after such repeated treatments a fresh dose of CBD can once again inactivate
erythromycin N-demethylase activity but not hexobarbital hydroxylase activity. The
resistance of hexobarbital hydroxylase to re-inactivation by CBD was paralleled by
stimulation of pentoxyresorufin O-dealkylase activity and the appearance of a 50 kD
protein that was immunoreactive to an antibody raised against rat hepatic cytochrome
P-450b. CBD metabolism in vitro by microsomes prepared from such CBD-"induced" animals,
resulted in a pattern of metabolites different from that observed from comparable
incubations with liver microsomes from either untreated or phenobarbital-treated animals.
Thus, it appears that CBD initially inactivates at least one cytochrome P-450 isozyme,
but after repetitive CBD treatment, an isozyme is induced that is resistant to further
re-inactivation by CBD. This isozyme appears to be immunochemically similar to, but
somewhat functionally distinct from, the isozyme induced by phenobarbital treatment
in mice.