Cannabis (Cannabis sativa)
Cannabidiol induces expression of human cytochrome P450 1A1 that is possibly mediated through aryl hydrocarbon receptor signaling in HepG2 cells
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Aims: 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.
Main methods: The expression of CYP1A1 and the aryl hydrocarbon receptor (AhR) was measured by a quantitative real-time polymerase chain reaction and/or Western blotting. Key findings: 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.
Significance: These results showed that CBDmay 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.
1 . Induction of CYP1A1 mRNA expression by 50 µM cannabidiol (id=NPDI-4qS0VQ)
In Vitro Enzyme Induction Experiment
Induction was detected. Cutoff used —
"The significance of differences between the means of the various groups was evaluated by means of a one-way analysis of variance followed by Bonferroni or Dunnett's post-hoc test."
- CYP1A1 4173297
Cell system HepG2 cell line
Results
Figure 2
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
mRNA expression
1000000 cells/well
Yes
0, 5, 10, 25, 50 µM
6 h
Platinum® SYBR® Green qPCR SuperMix-UDG qPCR (Invitrogen)
2 . Induction of CYP1A1 mRNA expression by 50 µM delta-9-THC (id=NPDI-qHswZw)
In Vitro Enzyme Induction Experiment
Induction was detected. Cutoff used —
"The significance of differences between the means of the various groups was evaluated by means of a one-way analysis of variance followed by Bonferroni or Dunnett's post-hoc test."
- CYP1A1 4173297
Cell system HepG2 cell line
Results
Figure 2
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
mRNA expression
1000000 cells/well
Yes
0, 5, 10, 25, 50 µM
6 h
Platinum® SYBR® Green qPCR SuperMix-UDG qPCR (Invitrogen)
3 . Non-induction of CYP1A1 mRNA expression by 50 µM cannabinol (id=NPDI-jW07Iw)
In Vitro Enzyme Induction Experiment
Non-induction was detected. Cutoff used —
"The significance of differences between the means of the various groups was evaluated by means of a one-way analysis of variance followed by Bonferroni or Dunnett's post-hoc test."
- CYP1A1 4173297
Cell system HepG2 cell line
Results
Estimated from Figure 2
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
mRNA expression
1000000 cells/well
Yes
0, 5, 10, 25, 50 µM
6 h
Platinum® SYBR® Green qPCR SuperMix-UDG qPCR (Invitrogen)