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Life Sci. 2015 Sep 1;136:87-93. doi: 10.1016/j.lfs.2015.07.007. Epub 2015 Jul 15.

Cannabidiol induces expression of human cytochrome P450 1A1 that is possibly mediated through aryl hydrocarbon receptor signaling in HepG2 cells.

Author information

1
Department of Pharmacy, Shinshu University Hospital, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
2
Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Ho-3, Kanagawa-machi, Kanazawa 920-1181, Japan.
3
Organization for Frontier Research in Preventive Pharmaceutical Sciences, Hokuriku University, Ho-3, Kanagawa-machi, Kanazawa 920-1181, Japan.
4
Department of Hygienic Chemistry, School of Pharmaceutical Sciences, Kyushu University of Health and Welfare, 1714-1 Yoshino-machi, Nobeoka 882-8508, Japan.
5
Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Ho-3, Kanagawa-machi, Kanazawa 920-1181, Japan; Organization for Frontier Research in Preventive Pharmaceutical Sciences, Hokuriku University, Ho-3, Kanagawa-machi, Kanazawa 920-1181, Japan. Electronic address: k-watanabe@hokuriku-u.ac.jp.

Abstract

AIMS:

We herein investigated the inducibility of cytochrome P450 1A1 (CYP1A1) by Δ(9)-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:

Δ(9)-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 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.

KEYWORDS:

AhR; CYP1A1; Cannabidiol; Induction; Marijuana; Protein tyrosine kinase

PMID:
26187180
DOI:
10.1016/j.lfs.2015.07.007
[Indexed for MEDLINE]

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