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Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes.
Life Sci 2011; 89(5-6):165-70LS

Abstract

AIMS

Cannabidiol (CBD), one of the major constituents in marijuana, has been shown to be extensively metabolized by experimental animals and humans. However, human hepatic enzymes responsible for the CBD metabolism remain to be elucidated. In this study, we examined in vitro metabolism of CBD with human liver microsomes (HLMs) to clarify cytochrome P450 (CYP) isoforms involved in the CBD oxidations.

MAIN METHODS

Oxidations of CBD in HLMs and recombinant human CYP enzymes were analyzed by gas chromatography/mass spectrometry.

KEY FINDINGS

CBD was metabolized by pooled HLMs to eight monohydroxylated metabolites (6α-OH-, 6β-OH-, 7-OH-, 1″-OH-, 2″-OH-, 3″-OH-, 4″-OH-, and 5″-OH-CBDs). Among these metabolites, 6α-OH-, 6β-OH-, 7-OH-, and 4″-OH-CBDs were the major ones as estimated from the relative abundance of m/z 478, which was a predominant fragment ion of trimethylsilyl derivatives of the metabolites. Seven of 14 recombinant human CYP enzymes examined (CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5) were capable of metabolizing CBD. The correlations between CYP isoform-specific activities and CBD oxidative activities in 16 individual HLMs indicated that 6β-OH- and 4″-OH-CBDs were mainly formed by CYP3A4, which was supported by inhibition studies using ketoconazole and an anti-CYP3A4 antibody. The correlation and inhibition studies also showed that CBD 6α-hydroxylation was mainly catalyzed by CYP3A4 and CYP2C19, whereas CBD 7-hydroxylation was predominantly catalyzed by CYP2C19.

SIGNIFICANCE

This study indicated that CBD was extensively metabolized by HLMs. These results suggest that CYP3A4 and CYP2C19 may be major isoforms responsible for 6α-, 6β-, 7-, and/or 4″-hydroxylations of CBD in HLMs.

Authors+Show Affiliations

Department of Hygienic Chemistry, Hokuriku University, Ho-3 Kanagawa-machi, Kanazawa, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21704641

Citation

Jiang, Rongrong, et al. "Identification of Cytochrome P450 Enzymes Responsible for Metabolism of Cannabidiol By Human Liver Microsomes." Life Sciences, vol. 89, no. 5-6, 2011, pp. 165-70.
Jiang R, Yamaori S, Takeda S, et al. Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes. Life Sci. 2011;89(5-6):165-70.
Jiang, R., Yamaori, S., Takeda, S., Yamamoto, I., & Watanabe, K. (2011). Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes. Life Sciences, 89(5-6), pp. 165-70. doi:10.1016/j.lfs.2011.05.018.
Jiang R, et al. Identification of Cytochrome P450 Enzymes Responsible for Metabolism of Cannabidiol By Human Liver Microsomes. Life Sci. 2011 Aug 1;89(5-6):165-70. PubMed PMID: 21704641.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes. AU - Jiang,Rongrong, AU - Yamaori,Satoshi, AU - Takeda,Shuso, AU - Yamamoto,Ikuo, AU - Watanabe,Kazuhito, Y1 - 2011/06/16/ PY - 2010/12/09/received PY - 2011/04/28/revised PY - 2011/05/12/accepted PY - 2011/6/28/entrez PY - 2011/6/28/pubmed PY - 2011/9/13/medline SP - 165 EP - 70 JF - Life sciences JO - Life Sci. VL - 89 IS - 5-6 N2 - AIMS: Cannabidiol (CBD), one of the major constituents in marijuana, has been shown to be extensively metabolized by experimental animals and humans. However, human hepatic enzymes responsible for the CBD metabolism remain to be elucidated. In this study, we examined in vitro metabolism of CBD with human liver microsomes (HLMs) to clarify cytochrome P450 (CYP) isoforms involved in the CBD oxidations. MAIN METHODS: Oxidations of CBD in HLMs and recombinant human CYP enzymes were analyzed by gas chromatography/mass spectrometry. KEY FINDINGS: CBD was metabolized by pooled HLMs to eight monohydroxylated metabolites (6α-OH-, 6β-OH-, 7-OH-, 1″-OH-, 2″-OH-, 3″-OH-, 4″-OH-, and 5″-OH-CBDs). Among these metabolites, 6α-OH-, 6β-OH-, 7-OH-, and 4″-OH-CBDs were the major ones as estimated from the relative abundance of m/z 478, which was a predominant fragment ion of trimethylsilyl derivatives of the metabolites. Seven of 14 recombinant human CYP enzymes examined (CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5) were capable of metabolizing CBD. The correlations between CYP isoform-specific activities and CBD oxidative activities in 16 individual HLMs indicated that 6β-OH- and 4″-OH-CBDs were mainly formed by CYP3A4, which was supported by inhibition studies using ketoconazole and an anti-CYP3A4 antibody. The correlation and inhibition studies also showed that CBD 6α-hydroxylation was mainly catalyzed by CYP3A4 and CYP2C19, whereas CBD 7-hydroxylation was predominantly catalyzed by CYP2C19. SIGNIFICANCE: This study indicated that CBD was extensively metabolized by HLMs. These results suggest that CYP3A4 and CYP2C19 may be major isoforms responsible for 6α-, 6β-, 7-, and/or 4″-hydroxylations of CBD in HLMs. SN - 1879-0631 UR - https://www.unboundmedicine.com/medline/citation/21704641/abstract/Identification_of_cytochrome_P450_enzymes_responsible_for_metabolism_of_cannabidiol_by_human_liver_microsomes_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0024-3205(11)00264-5 DB - PRIME DP - Unbound Medicine ER -