Structural Requirements for Potent Direct Inhibition of Human Cytochrome P450 1A1 by Cannabidiol: Role of Pentylresorcinol Moiety
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- Yamaori Satoshi
- Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University
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- Okushima Yoshimi
- Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University
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- Masuda Kazufumi
- Department of Physical Chemistry, Graduate School of Clinical Pharmacy, Shujitsu University
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- Kushihara Mika
- Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University
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- Katsu Takashi
- Department of Biophysical Chemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
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- Narimatsu Shizuo
- Department of Health Chemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
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- Yamamoto Ikuo
- Department of Hygienic Chemistry, School of Pharmaceutical Sciences, Kyushu University of Health and Welfare
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- Watanabe Kazuhito
- Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University Organization for Frontier Research in Preventive Pharmaceutical Sciences, Hokuriku University
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抄録
Our recent work has shown that cannabidiol (CBD) exhibits the most potent direct inhibition of human cytochrome P450 1A1 (CYP1A1) among the CYP enzymes examined. However, the mechanism underlying this CBD inhibition remains to be clarified. Thus, to elucidate the structural requirements for the potent inhibition by CBD, the effects of CBD and its structurally related compounds on CYP1A1 activity were investigated with recombinant human CYP1A1. Olivetol, which corresponds to the pentylresorcinol moiety of CBD, inhibited the 7-ethoxyresorufin O-deethylase activity of CYP1A1; its inhibitory effect (IC50=13.8 µM) was less potent than that of CBD (IC50=0.355 µM). In contrast, d-limonene, which corresponds to the terpene moiety of CBD, only slightly inhibited CYP1A1 activity. CBD-2′-monomethyl ether (CBDM) and CBD-2′,6′-dimethyl ether inhibited CYP1A1 activity with IC50 values of 4.07 and 23.0 µM, respectively, indicating that their inhibitory effects attenuated depending on the level of methylation on the free phenolic hydroxyl groups in the pentylresorcinol moiety of CBD. Cannabidivarin inhibited CYP1A1 activity, although its inhibitory potency (IC50=1.85 µM) was lower than that of CBD. The inhibitory effects of Δ9-tetrahydrocannabinol and cannabielsoin (IC50s ≈10 µM), which contain a free phenolic hydroxyl group and are structurally constrained, were less potent than that of CBDM, which contains a free phenolic hydroxyl group and is rotatable between pentylresorcinol and terpene moieties. These results suggest that the pentylresorcinol structure in CBD may have structurally important roles in direct CYP1A1 inhibition, although the whole structure of CBD is required for overall inhibition.
収録刊行物
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- Biological & Pharmaceutical Bulletin
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Biological & Pharmaceutical Bulletin 36 (7), 1197-1203, 2013
公益社団法人 日本薬学会
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詳細情報 詳細情報について
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- CRID
- 1390001204632558464
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- NII論文ID
- 130003361480
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- NII書誌ID
- AA10885497
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- COI
- 1:STN:280:DC%2BC3sjmsVKltA%3D%3D
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- ISSN
- 13475215
- 09186158
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- NDL書誌ID
- 024644777
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- PubMed
- 23811569
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- 本文言語コード
- en
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- データソース種別
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- JaLC
- NDL
- Crossref
- PubMed
- CiNii Articles
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- 使用不可