Comparison in the In Vitro Inhibitory Effects of Major Phytocannabinoids and Polycyclic Aromatic Hydrocarbons Contained in Marijuana Smoke on Cytochrome P450 2C9 Activity
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- YAMAORI Satoshi
- Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University
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- KOEDA Kyoko
- Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University
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- KUSHIHARA Mika
- Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University
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- HADA Yui
- Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku 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
書誌事項
- タイトル別名
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- Comparison in the <i>In Vitro</i> Inhibitory Effects of Major Phytocannabinoids and Polycyclic Aromatic Hydrocarbons Contained in Marijuana Smoke on Cytochrome P450 2C9 Activity
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抄録
Inhibitory effects of Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD), and cannabinol (CBN), the three major constituents in marijuana, and polycyclic aromatic hydrocarbons (PAHs) contained in marijuana smoke on catalytic activity of human cytochrome P450 (CYP) 2C9 were investigated. These phytocannabinoids concentration-dependently inhibited S-warfarin 7-hydroxylase and diclofenac 4′-hydroxylase activities of human liver microsomes (HLMs) and recombinant CYP2C9 (rCYP2C9). In contrast, none of the twelve PAHs including benz[a]anthracene and benzo[a]pyrene exerted substantial inhibition (IC50 > 10 µM). The inhibitory potentials of Δ9-THC (Ki = 0.937–1.50 µM) and CBN (Ki = 0.882–1.29 µM) were almost equivalent regardless of the enzyme sources used, whereas the inhibitory potency of CBD (Ki = 0.954–9.88 µM) varied depending on the enzyme sources and substrates used. Δ9-THC inhibited both S-warfarin 7-hydroxylase and diclofenac 4′-hydroxylase activities of HLMs and rCYP2C9 in a mixed manner. CBD and CBN competitively inhibited the activities of HLMs and rCYP2C9, with the only notable difference being that CBD and CBN exhibited mixed-type inhibitions against diclofenac 4′-hydroxylation and S-warfarin 7-hydroxylation, respectively, by rCYP2C9. None of Δ9-THC, CBD, and CBN exerted metabolism-dependent inhibition. These results indicated that the three major phytocannabinoids but not PAHs contained in marijuana smoke potently inhibited CYP2C9 activity and that these cannabinoids can be characterized as direct inhibitors for CYP2C9.<br>
収録刊行物
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- Ｄｒｕｇ Ｍｅｔａｂｏｌｉｓｍ ａｎｄ Ｐｈａｒｍａｃｏｋｉｎｅｔｉｃｓ
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Ｄｒｕｇ Ｍｅｔａｂｏｌｉｓｍ ａｎｄ Ｐｈａｒｍａｃｏｋｉｎｅｔｉｃｓ 27 (3), 294-300, 2012
日本薬物動態学会