著者

Satoshi Yamaori Yoshimi Okushima Kazufumi Masuda Mika Kushihara Takashi Katsu Shizuo Narimatsu Ikuo Yamamoto Kazuhito Watanabe

出版者

公益社団法人日本薬学会

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.36, no.7, pp.1197-1203, 2013-07-01 (Released:2013-07-01)

参考文献数

39

被引用文献数

2 15

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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.

著者

Rongrong JIANG Satoshi YAMAORI Yasuka OKAMOTO Ikuo YAMAMOTO Kazuhito WATANABE

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

Drug Metabolism and Pharmacokinetics (ISSN:13474367)

巻号頁・発行日

vol.28, no.4, pp.332-338, 2013 (Released:2013-08-25)

参考文献数

49

被引用文献数

151

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The present study investigated the inhibitory effect of cannabidiol (CBD), a major constituent of marijuana, on the catalytic activity of cytochrome P450 2C19 (CYP2C19). (S)-Mephenytoin 4′-hydroxylase activities of human liver microsomes (HLMs) and recombinant CYP2C19 were inhibited by CBD in a concentration-dependent manner (IC50 = 8.70 and 2.51 µM, respectively). Omeprazole 5-hydroxylase and 3-O-methylfluorescein O-demethylase activities in recombinant CYP2C19 were also strongly inhibited by CBD (IC50 = 1.55 and 1.79 µM, respectively). Kinetic analysis for inhibition revealed that CBD showed a mixed-type inhibition against (S)-mephenytoin 4′-hydroxylation by recombinant CYP2C19. To clarify the structural requirements for CBD-mediated CYP2C19 inhibition, the effects of CBD-related compounds on CYP2C19 activity were examined. Olivetol inhibited the (S)-mephenytoin 4′-hydroxylase activity of recombinant CYP2C19 with the IC50 value of 15.3 µM, whereas d-limonene slightly inhibited the activity (IC50 > 50 µM). The inhibitory effect of CBD-2′-monomethyl ether (IC50 = 1.88 µM) on CYP2C19 was comparable to that of CBD, although the inhibitory potency of CBD-2′,6′-dimethyl ether (IC50 = 14.8 µM) was lower than that of CBD. Cannabidivarin, possessing a propyl side chain, showed slightly less potent inhibition (IC50 = 3.45 µM) as compared with CBD, whereas orcinol and resorcinol did not inhibit CYP2C19 activity at all. These results indicate that CBD caused potent CYP2C19 inhibition, in which one free phenolic hydroxyl group and the pentyl side chain of CBD may play important roles.

著者

Satoshi YAMAORI Kyoko KOEDA Mika KUSHIHARA Yui HADA Ikuo YAMAMOTO Kazuhito WATANABE

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

Drug Metabolism and Pharmacokinetics (ISSN:13474367)

巻号頁・発行日

vol.27, no.3, pp.294-300, 2012 (Released:2012-06-25)

参考文献数

38

被引用文献数

97

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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.

著者

山本 郁男 岩井 勝正 井本 真澄 宇佐見 則行 ヤマモト イクオ イワイ カツマサ イモト マスミ ウサミ ノリユキ Ikuo YAMAMOTO Katsumasa IWAI Masumi IMOTO Noriyuki USAMI

雑誌

九州保健福祉大学研究紀要 = Journal of Kyushu University of Health and Welfare

巻号頁・発行日

vol.6, pp.277-285, 2005-03-25

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The School of Pharmaceutical Sciences, Kyushu University of Health and Welfare located in Nobeoka City, Miyazaki Prefecture wa founded in April, 2003. This place (Nobeoka) wa famous to be called Himuka(Hyuga), an ancient name, since several handred years ago. Himuka is still used in the historical and sightseeing books. However, it was no reasons why the School of Pharmaceutical Sciences did start at this place, Nobeoka. So, we searched all over the place(Himuka) for some people related to Pharmaceuticla Sciences. As results, Kitsumon AKIZUKI(1989-1981) who lived in Nobeoka during Edo period was picked out among several persons. Although he stayed in Nobeoka only for two years, he had done many great things concerned tin the education, medicine, botany, herbalism, philology and political events. Especially, Kitsumon AKIZUKI invited Hika KAKU, a famous herbalist, from Azimu, Usa (Oita prefecture) and let him investigate and herborize the local herbs near Nobeoka. This paper deals with Kitsumon AKIZUKI and his achievement in his life.