Effect of cannabidiol on cytochrome P-450 isozymes

doi:10.1016/0006-2952(89)90432-2

Biochemical Pharmacology

Volume 38, Issue 17, 1 September 1989, Pages 2789-2794

https://doi.org/10.1016/0006-2952(89)90432-2 Get rights and content

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 6β-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 RD 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.

References (21)

AJ Siemens et al.
Effect of cannabis on pentobarbital-induced sleeping time and pentobarbital metabolism in the rat
Biochem Pharmacol
(1974)
K Watanabe et al.
Self-catalyzed inactivation of cytochrome P-450 during microsomal metabolism of cannabidiol
Biochem Pharmacol
(1987)
R Karler et al.
The pharmacokinetic fate of cannabidiol and its relationship to barbiturate sleep time
Biochem Pharmacol
(1979)
OH Lowry et al.
Protein measurement with the Folin phenol reagent
J Biol Chem
(1951)
RA Lubet et al.
Dealkylation of pentoxyresorufin: a rapid and sensitive assay for measuring induction of cytochrome(s) P-450 by phenobarbital and other xenobiotics in the rat
Arch Biochem Biophys
(1985)
DJ Waxman et al.
Regioselectivity and stereoselectivity of androgen hydroxylations catalyzed by cytochrome P-450 isozymes purified from phenobarbital-induced rat liver
J Biol Chem
(1983)
HK Borys et al.
Cannabidiol and Δ⁹-tetrahydrocannabinol metabolism
Biochem Pharmacol
(1979)
WDM Paton et al.
Effect of cannabis and certain of its constituents on pentobarbitone sleeping time and phenazone metabolism
Br J Pharmacol
(1972)
M Fernandes et al.
Cannabinoids and hexobarbital induced loss of righting reflexes
Naunyn-Schmiedebergs Arch Pharmacol
(1974)
HK Borys et al.
Development of tolerance to the prolongation of hexobarbitone sleeping time caused by cannabidiol
Br J Pharmacol
(1979)

There are more references available in the full text version of this article.

Cited by (40)

Cannabidiol induces expression of human cytochrome P450 1A1 that is possibly mediated through aryl hydrocarbon receptor signaling in HepG2 cells
2015, Life Sciences
Citation Excerpt :
We herein demonstrated that CBD induced the expression of CYP1A1 in HepG2 cells; inducibility by CBD was more potent than that by Δ9-THC. To the best of our knowledge, this is the first study to show the induction of CYP1A expression by CBD; however, the phytocannabinoid is known to be an inducer of CYP2B and CYP3A enzymes in mouse livers [26]. The mean contents of Δ9-THC and CBD in dried plant preparations of marijuana confiscated in the United States were estimated to be 4.5% and 0.4%, respectively, although these contents varied widely [27].
We herein investigated the inducibility of cytochrome P450 1A1 (CYP1A1) by Δ⁹-tetrahydrocannabinol, cannabidiol (CBD), and cannabinol, three major phytocannabinoids, using human hepatoma HepG2 cells.
The expression of CYP1A1 and the aryl hydrocarbon receptor (AhR) was measured by a quantitative real-time polymerase chain reaction and/or Western blotting.
Δ⁹-Tetrahydrocannabinol and CBD concentration-dependently induced the expression of CYP1A1 mRNA, whereas cannabinol showed little or no induction. Among the phytocannabinoids tested, CBD was the most potent inducer of CYP1A1 expression. The induction of CYP1A1 expression by CBD was significantly attenuated by the knockdown of AhR expression with AhR small interfering RNAs. The role of protein tyrosine kinases (PTKs) in the CBD-mediated induction of CYP1A1 was then examined using herbimycin A, a PTK inhibitor. The upregulation of CYP1A1 by CBD was significantly suppressed by herbimycin A as was the induction by omeprazole but not 3-methylcholanthrene. The inducibility of CYP1A1 by CBD-related compounds was examined to clarify the structural requirements for CBD-mediated CYP1A1 induction. Olivetol, which corresponds to the pentylresorcinol moiety of CBD, significantly induced the expression of CYP1A1, whereas d-limonene, CBD-2′-monomethyl ether, and CBD-2′,6′-dimethyl ether did not.
These results showed that CBD may have induced human CYP1A1 expression through the activation of PTK-dependent AhR signaling, in which two phenolic hydroxyl groups in the pentylresorcinol moiety of CBD may play structurally important roles.
Cannabinoid physiology and pharmacology: 30 Years of progress
2004, Neuropharmacology
Δ⁹-Tetrahydrocannabinol from Cannabis sativa is mimicked by cannabimimetic analogs such as CP55940 and WIN55212-2, and antagonized by rimonabant and SR144528, through G-protein-coupled receptors, CB₁ in the brain, and CB₂ in the immune system. Eicosanoids anandamide and 2-arachidonoylglycerol are the “endocannabinoid” agonists for these receptors. CB₁ receptors are abundant in basal ganglia, hippocampus and cerebellum, and their functional activity can be mapped during behaviors using cerebral metabolism as the neuroimaging tool. CB₁ receptors couple to G_i/o to inhibit cAMP production, decrease Ca²⁺ conductance, increase K⁺ conductance, and increase mitogen-activated protein kinase activity. Functional activation of G-proteins can be imaged by [35S]GTPγS autoradiography. Post-synaptically generated endocannabinoids form the basis of a retrograde signaling mechanism referred to as depolarization-induced suppression of inhibition (DSI) or excitation (DSE). Under circumstances of sufficient intracellular Ca²⁺ (e.g., burst activity in seizures), synthesis of endocannabinoids releases a diffusible retrograde messenger to stimulate presynaptic CB₁ receptors. This results in suppression of γ-aminobutyric acid (GABA) release, thereby relieving the post-synaptic inhibition. Tolerance develops as neurons adjust both receptor number and cellular signal transduction to the chronic administration of cannabinoid drugs. Future therapeutic drug design can progress based upon our current understanding of the physiology and pharmacology of CB₁, CB₂ and related receptors. One very important role for CB₁ antagonists will be in the treatment of craving in the disease of substance abuse.
Effects of unsaturated side-chain analogs of tetrahydrocannabinol on cytochromes P450
2000, Biochemical Pharmacology
Citation Excerpt :
Mice were treated with Tween 80 vehicle or THC analog (60 mg/kg) for 2 hr. Animals were killed by cervical dislocation, livers were removed, and microsomes were prepared [22]. Hepatic microsomes (0.2 mg protein/mL) were incubated with THC (130 μM) and NADPH (1 mM) at 37° for 10 min before extraction with ethyl acetate (as described above) to determine THC metabolite formation.
The ability of unsaturated side-chain analogs of Δ⁸-tetrahydrocannabinol (THC) to selectively inactivate mouse hepatic cytochromes P450 3A11 and 2C29 was examined. THC side-chain analogs were preincubated with mouse hepatic microsomes and NADPH for various times before dilution and determination of Δ⁹-THC metabolism specific for P450s 3A11 and 2C29. THC-enyl analogs had little or no effect on P450 3A11 but inactivated P450 2C29 in a time-dependent manner, with approximately 50% inactivation observed after a 30-min preincubation. THC-ynyl analogs were less selective in their P450 inactivation but appeared to be more effective than their corresponding enyl analogs. THC-ynyl analogs inactivated P450s 3A11 and 2C29 in a time-dependent manner and could inactive 40–80% of their activities after a 30-min preincubation. The THC-ynyl analogs were nearly as effective as cannabidiol, a well-characterized inactivator of these mouse P450s. Despite their ability to inactivate P450 in vitro, neither the THC-enyl nor the THC-ynyl analogs were very effective after in vivo administration. Unsaturated side-chain THC analogs may be useful in the development of specific P450 inactivators.
Chronic cannabinoid, CP-55,940, administration alters biotransformation in the rat
1996, European Journal of Pharmacology
The objective of this study was to investigate the effects of single and repeated administration of CP-55,940 {(−)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)-phenyl]-trans-4-(3-hydroxypropyl)cyclohexandol)} on behavior, energy metabolism and biotransformation. Single intraperitoneal administration to male Sprague-Dawley rats of CP-55,940 (0.4 mg/kg), induced a behavioural response characterized by ‘splayed hind limbs’, antinociception, hypothermia and a decrease in locomotor activity. Brain and liver mitochondria of the CP-55,940-treated rats exhibited an increase in respiration and no changes in $ADP O$ and citrate synthase specific activity. Repeated intraperitoneal administration of CP-55,940 (0.4 mg/kg, 11 days) induced behavioural tolerance, disappearance of the increase in the mitochondrial oxygen consumption as well as an increase in the monooxygenase activities and the content of liver microsomal cytochrome P450. Some hepatic metabolizing enzymes of the cytosolic glutathione-centre system were also affected. Previous studies had indicated that the tolerance after chronic administration of CP-55,940 could be due to down-regulation of brain cannabinoid receptors. The present findings demonstrate that the behavioural tolerance occurs together with modified biotransformation activities.
Use of cannabis in the treatment of animals: A systematic review of randomized clinical trials
2022, Animal Health Research Reviews
Twice-daily oral administration of a cannabidiol and cannabidiolic acid–rich hemp extract was well tolerated in orange-winged Amazon parrots (Amazona amazonica) and has a favorable pharmacokinetic profile
2023, American Journal of Veterinary Research

View all citing articles on Scopus

View full text

Effect of cannabidiol on cytochrome P-450 isozymes

Abstract

Biochem Pharmacol

Biochem Pharmacol

Biochem Pharmacol

J Biol Chem

Arch Biochem Biophys

J Biol Chem

Biochem Pharmacol

Effect of cannabis and certain of its constituents on pentobarbitone sleeping time and phenazone metabolism

Br J Pharmacol

Cannabinoids and hexobarbital induced loss of righting reflexes

Naunyn-Schmiedebergs Arch Pharmacol

Development of tolerance to the prolongation of hexobarbitone sleeping time caused by cannabidiol

Br J Pharmacol