Polymorphic drug-metabolizing enzymes of anesthetics agent propofol rekated to its infusion syndrome.

• Project/Area Number: 19591819
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Anesthesiology/Resuscitation studies
• Research Institution: Showa Pharmaceutical University
• Principal Investigator: MURAYAMA Norie Showa Pharmaceutical University, 薬学部, 助教 (90219949)
• Co-Investigator(Kenkyū-buntansha): YAMAZAKI Hiroshi 昭和薬科大, 薬学部, 教授 (30191274) ; SHIMIZU Makiko 昭和薬科大, 薬学部, 助教 (90307075)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2008: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2007: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: 麻酔学 / プロポフォール / CYP2B6 / 遺伝子多型 / 覚醒遅延 / CYP2B6*6 / P450

Research Abstract

ヒト肝ミクロゾームでのプロポフォール水酸化酵素活性に個人差が認められ、さらにその要因として各個体のP450分子種含量の違いが考えられたことから、4-水酸化およびω-水酸化酵素活性とCYP2B6およびCYP3A4含量との相関性について検討を行なった。その結果プロポフォール4-水酸化活性と、CYP2B6含量に最も高い相関性が認められ(r=0.84)ついでCYP3A4含量との間に相関性が認められた。一方、プロポフォールω-水酸化活性とCYP2B6含量との間に高い相関性認められた。個体間での含量の変動には遺伝的多型の影響が考えられたことから、これまで報告されているCYP2B6に関する遺伝子多型のうちで、活性低下を伴うCYP2B6*6とCYP2B6*9に関して検討を行なったところ、CYP2B6*6をホモ変異で有している場合、通常のおよそ1/2の活性低値を示し,明らかに多型との関連性が示唆された。一方、CYP2B6*9ホモ変異で有する場合でも酵素活性の著しい低下は認められなかった。このことから、CYP2B6の516変異がプロポフォールの代謝を考える上で重要な因子であると考えられた。アジア系人種ではこの変異の発現頻度は比較的高いことから、臨床でのプロポフォール処置時の覚醒遅延の危険性を評価するうえで、本成果は有効な情報であると示唆された。そこで、実際にプロポフォール麻酔施行患者の血中プロポフォール濃度推移を測定するための条件および迅速な測定系を確立した。これまで行なわれていた煩雑な抽出法を改良した蛍光検出器を用いた測定系は臨床現場での実施に充分適応できると考えられた。

Research Products

• [Journal Article] Utilization of estimated physicochemical properties as an integrated part of predicting hepatic clearance in the early drug discovery stage: The impact of plasma and microsomal binding (2009)
  • Author(s): Chie Emoto, Norie Murayama Rostami-Hodjegan, A. and Hiroshi Yamazaki
  • Journal Title: Xenobiotica 39 Pages: 227-235
  • Peer Reviewed
• [Journal Article] Utilization of estimated physicochemical properties as an integrated part of predicting hepatic clearance in the early drug discovery stage : The impact of plasma and microsomal binding (2009)
  • Author(s): Emoto, C., Murayama, N. Rostami-Hodjegan, A., Yamazaki, H
  • Journal Title: Xenobiotica 39 Pages: 227-235
  • Peer Reviewed
• [Journal Article] Effects of enzyme sources on midazolam 1'-hydroxylation activity catalyzed by recombinant cytochrome P450 3A4 in combination with NADPH- cyto- chrome P450 reductase (2008)
  • Author(s): Chie Emoto, Norie Murayama, and Hiroshi Yamazaki
  • Journal Title: Drug Metab.Lett., 2 Pages: 190-192
  • Peer Reviewed
• [Journal Article] Comparison of kinetic parameters for drug oxidation rates and substrate inhibition potential mediated by cytochrome P450 3A4 and 3A5 (2008)
  • Author(s): Niwa, T., Murayama, N., Emoto, C., and Yamazaki, H
  • Journal Title: Current Drug Metabolism 9 Pages: 20-33
  • Peer Reviewed
• [Journal Article] Heterotropic cooperativity in oxidation mediated by cytochrome P450 (2008)
  • Author(s): Niwa, T., Murayama, N., and Yamazaki, H
  • Journal Title: Curr.Drug Metab. 9 Pages: 453-462
  • Peer Reviewed
• [Journal Article] Interaction of polycyclic aromatic hydrocarbons with human cytochrome P450 1B1 in Inhibiting catalytic activity (2008)
  • Author(s): Shimada, T. Murayama, N., Tanaka, K., Takenaka, S., Imai, Y., Hopkins, E., Foroozesh, M. K., Al worth, W. L., Yamazaki, H., Guengerich, F. P, Komori, M
  • Journal Title: Chem. Res Toxicol 21 Pages: 2313-2323
  • Peer Reviewed
• [Journal Article] Effects of enzyme sources on midazolam 1'-hydroxylation activity catalyzed by recombinant cytochrome P450 3A4 in combination with NADPH-cytochrome P450 reductase. (2008)
  • Author(s): Emoto, C., Murayama, N., Yamazaki, H.
  • Journal Title: Drug Metab. Lett. 2 Pages: 190-192
• [Journal Article] Guengerich, F.P., and Yamazaki, H. Involvement of human cytochrome P450 2B6 in the omega- and 4-hydroxylation of the anesthetic agent propofol (2007)
  • Author(s): Murayama, N., Minoshima, M., Shimizu, M
  • Journal Title: Xenobiotica 37 Pages: 717-724
  • Peer Reviewed
• [Journal Article] Different mechanisms for inhibition of human cytochromes P450 1A1,1A2,and IBl by polycyclic aromatic inhibitors. (2007)
  • Author(s): Shimada, T., Murayama, N., Okuda, K., Funae, Y., Yamazaki.H., and Guengerich, F.P.
  • Journal Title: Chem.Res.Toxicol. 20 Pages: 489-496
  • Peer Reviewed
• [Journal Article] Roles of CYP3A4 and CYP2C19 in methylhydroxylated and N-oxidized metabolite formation from voriconazole,a new anti-fungal agent,in humanlive rmicrosomes. (2007)
  • Author(s): Murayama, N., Imai, N., Nakane, T., Shimizu, M., and Yamazaki, H.
  • Journal Title: Biochem.Pharmacol 73 Pages: 2020-2026
  • Peer Reviewed
• [Journal Article] Involvement of human cytochrome P450 2B6 in the □-and 4-hydroxylation of the a nesthetic agent propofol. (2007)
  • Author(s): Murayama, N., Minoshima, M., Shimizu, M., Guengerich, F.P., and Yamazaki, H.
  • Journal Title: Xenobiotica 37 Pages: 717-724
  • Peer Reviewed
• [Journal Article] Effect of genetic variants of the human flavin-containing monooxygenase 3 (FMO3) on N-and S-oxygenation activities (2007)
  • Author(s): Shimizu, M., Yano, H., Nagashima, S.Murayama, N., Zhang, J., Cashman, J.R. and Yamazaki, H
  • Journal Title: Drug Metab.Dispos 35 Pages: 328-330
  • Peer Reviewed
• [Journal Article] Missense and Nonsense Mutations of the Flavin-containing Monooxygenase 3 Gene in a Japanese Cohort (2007)
  • Author(s): Shimizu, M.Tbmioka, S., Murayama, N. and Yamazaki, H.
  • Journal Title: Drug Metab.Pharmacokinet. 22 Pages: 61-64
  • NAID: 10018733032
  • Peer Reviewed
• [Presentation] アゾール系抗真菌薬の阻害効果とCYP3A5遺伝子多型との関連性 (2009)
  • Author(s): 村山典恵、中本実那子、岡田雄介、清水万紀子、山崎浩史
  • Organizer: 日本薬学会第129回年会
  • Place of Presentation: 京都
• [Presentation] アゾール系抗真菌薬の薬物酸化的代謝に及ぼす影響 (2008)
  • Author(s): 中本実那子、村山典恵、清水万紀子、山崎浩史
  • Organizer: 第56回聖マリアンナ医学会学術集会
  • Place of Presentation: 川崎
• [Presentation] 全身性麻酔薬プロポフォールの酸化的代謝における個人差 (2008)
  • Author(s): 中本実那子、村山典恵、神作文康、柏田雅也、簑島正樹、清水万紀子、山崎浩史
  • Organizer: 第29回日本臨床薬理学会年会
  • Place of Presentation: 東京
• [Presentation] "Micromini" Pigs as a Possible New Animal Model For Humans in Non-Clinical Study (2008)
  • Author(s): Norie Murayama, Naoki Kaneko, Kana Horiuchi, Makiko Shimizu, Katzuhiko Ito, and Hiroshi Yamazaki
  • Organizer: 23^<rd> JSSX Annual Meeting
  • Place of Presentation: 熊本
• [Presentation] ヒト肝チトクロムP450による全身麻酔薬プロポフォールの代謝について (2008)
  • Author(s): 中本実那子、村山典恵、簑島正樹、清水万紀子、山崎浩史
  • Organizer: 医療薬学フォーラム2008 第16回クリニカルファーマシーシンポジウム
  • Place of Presentation: 船橋
• [Presentation] ヒト肝チトクロムP450による全身性麻酔薬プロポフォールの代謝について (2008)
  • Author(s): 中本実那子, 村山典恵, 簑島正樹, 清水万紀子, 山崎浩史
  • Organizer: 医療薬学フォーラム2008
  • Place of Presentation: 船橋
• [Presentation] INDIVIDUAL DIFFERENCES OF OXIDATIVE METABOLISM OF MEDICINES AND THEIR CLINICAL SIGNIFICANCE (2008)
  • Author(s): Hiroshi Yamazaki, ^a Dimitrios Zonios, ^b Makiko Shimizu, ^a John Bennett, ^b Norie Murayama
  • Organizer: Pan-Pacific International Partnership Conference on Pharm aceutical and Life Sciences The 4th US-Japan Joint Conference
  • Place of Presentation: 名古屋
• [Presentation] ヒト肝チトクロームP450触媒活性に及ぼすサリドマイドの影響 (2008)
  • Author(s): 村山 典恵、柳田 千裕、清水 万紀子、山崎 浩史
  • Organizer: 日本薬学会第128年会
  • Place of Presentation: 横浜
• [Presentation] Omega- and 4-Hydroxylation of the Anesthetic Agent Propofol Catalyzed by Human Liver Microsomal Cytochrome P450 2B6 (2007)
  • Author(s): Norie Murayama , Masaki Minoshima, Makiko Shimizu, F.Peter Guengerich, and Hiroshi Yamazaki
  • Organizer: 22nd JSSX/ 8th ISSX meeting
  • Place of Presentation: 仙台
• [Presentation] 全身性プロポフォールの覚醒遅延に関するヒト肝薬物代謝酵素の検討 (2007)
  • Author(s): 村山典恵、簑島正樹、今井直子、清水万紀子、山崎浩史
  • Organizer: 第127会日本薬学年会
  • Place of Presentation: 富山
• [Presentation] Omega-and 4-Hydroxylation of the Anesthetic Agent Propofol Catalyzed by Human Liver Microsomal Cytochrome P450 2B6 (2007)
  • Author(s): Norie Murayama, Masaki Minoshima, Makiko Shimizu, F.Peter Guengerich, and Hiroshi Yamazaki
  • Organizer: 22nd JSSX/ 8th ISSX meeting
  • Place of Presentation: 仙台
• [Presentation] Voriconazole methyl hydroxylation and N-oxidation catalyzed by CYP3A4 and CYP2C19 in human liver microsomes (2007)
  • Author(s): Hiroshi Yamazaki, Norie Murayama, Naoko Imai, Takahisa Nakane, Makiko Shimizu
  • Organizer: 22nd JSSX/ 8th ISSX meeting
  • Place of Presentation: 仙台
• [Remarks]
  • URL: http://www.shoyaku.ac.jp/labosite/doutai/index.html