2007 Fiscal Year Final Research Report Summary
Molecular mechanism of chemical-induced toxicity in fetal livers
| Project/Area Number |
17390034
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Environmental pharmacy
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| Research Institution | Showa Pharmaceutical University |
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Principal Investigator |
YAMAZAKI Hiroshi Showa Pharmaceutical University, Dept. of Pharmacy, Professor (30191274)
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| Co-Investigator(Kenkyū-buntansha) |
SHIMIZU Makiko Showa Pharmaceutical University, Depf. Of Pharmacy, Assistant Professor (90307075)
MURAYAMA Norie Showa Pharmaceutical University, Depf of Pharmacy, Assistant Professor (90219949)
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| Project Period (FY) |
2005 – 2007
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| Keywords | Toxicity / P450 / CYP2B6 / Metabolic activation / Thalidomide / Voriconazole / Pronofol / CYP3A |
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| Research Abstract |
We found several new results of drug metabolism in human liver microsomes. 1) Voriconazole ((2R, 3S)-2-(2, 4-difluorophenyI)-3-(5-fluoro-4-pyrimidiny1)-1-(1H-1, 2, 4-triazol-1-yl)-2-butanol) is a new antifungal agent developed as oral and intravenous formulations. In vivo studies in humans have indicated that voriconazole is extensively metabolized with less than 2% of the dose excreted unchanged. Involvement of cytochrome CYP2C19, CYP2C9, and CYP3A4 in N-oxidation of voriconazole has been demonstrated using human liver microsomes. To confirm the precise roles of P450 isoforms in voriconazole clearance in individuals, we investigated the oxidative metabolism of voriconazole catalyzed by recombinant P450s as well as human liver microsomes genotyped for the CYP2C19 gene. Among recombinant P450 isoforms using Escherichia coli expression systems, CYP2C19 and CYP3A4 had voriconazole N-oxidation activities, but not CYP2C9
2) Propofol (2, 6-diisopropylphenol) is administered for the induction
… More
of anesthesia and maintenance of anesthesia or for sedation. The merit of rapid and complete recovery that occurs even after relatively prolonged intravenous infusions of propofol is attributable to the extensive biotransformation of the parent compound, primarily in the liver. However, a significant association with the development of progressive myocardial failure has been reported for long-term and high-dose propofol infusion. Although there are several reports on the propofol pharmacokinetics and drug interactions in humans, the roles of individual P450 enzymes in the propofol disposition are still unknown. In the present study, the roles of human P450 enzymes involved in propofol 4- and ω-hydroxylation were investigated with recombinant human P450s and liver microsomes. CYP2B6 and CYP1A2, followed CYP3A4, showed high activities of propofol 4-hydroxylation in recombinant human P450 enzyme systems. In the contrast, ω-hydroxylation of propofol was mainly catalyzed by CYP2B6.
3) Thalidomide is a promising drug in the treatment of a number of cancers and inflammatory diseases. On the other hand, a little information was reported regarding effects on metabolizing enzymes. We investigated the effects of thalidomide on cytochrome P450 in human liver microsomes. The present results suggest that total midazolam clearance would be increased in a dose dependent manner. Thalidomide may cause drug interactions of co-administered medicines Less
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[Journal Article] Molecular evolution and balancing selection in the flavin-containing monooxygenase3 gene(FMO3)2008
Author(s)
Allerston, C.K., Shimizu, M., Fujieda, M., Shephard, E.A., Yamazaki, H. and Phillips, I.R.
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Journal Title
Pharmacogenet.Genomics 17
Pages: 827-839
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] Roles of CYP3A4 and CYP2C19 in methylhydroxylated and N-oxidized metabolite for mation from voriconazole,a new anti-fungal agent,in human liver microsomes2007
Author(s)
Murayama, N., Imai, N., Nakane, T., Shimizu, M., and Yamazaki, H.
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Journal Title
Biochem.Pharmacol. 73
Pages: 2020-2026
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] Effect of genetic variants of the human flavin-containing monooxygenase 3(FMO3)on N- and S-oxygenation activities2007
Author(s)
Shimizu, M., Yano, H., Nagashima, S., Murayama, N., Zhang, J., Cashman, J.R. and Yamazaki, H
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Journal Title
Drug Metab.Dispos 35
Pages: 328-330
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] Disparity in holo/apoprotein ratios of different standards used for immunoqu antification of hepatic cytochrome P450 enzymes2007
Author(s)
Perrett, H.F., Barter, Z.E., Jones, B.C., Yamazaki, H., Tucker, G.T., and Rostami-Hodjegan, A.
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Journal Title
Drug Metab.Dispos 35
Pages: 1733-1736
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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-
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[Journal Article] Effect of genetic variants of the human flavin-containing monooxygenase 3(FMO3) on N- and S-oxygenation activities2007
Author(s)
Shimada, T., Murayama, N., Okuda, K., Funae, Y., Yamazaki, H., and Guengerich, F.P.
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Journal Title
Chem.Res.Toxicol. 20
Pages: 489-496
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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-
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[Journal Article] Different mechanisms for inhibition of human cytochromes P450 1A1,1A2,and 1B1 by polycyclic aromatic inhibitors2007
Author(s)
Shimada, T., Murayama, N., Okuda, K., Funae, Y., Yamazaki, H., and Guengerich, F.P
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Journal Title
Chem.Res.Toxicol. 20
Pages: 489-496
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
-
-
[Journal Article] Roles of CYP3A4 and CYP2C19 in methylhydroxylated and N-oxidized metabolite formation from voriconazole, a new anti-fungal agent, in human liver microsomes2007
Author(s)
Murayama, N., Imai, N., Nakane, T., Shimizu, M., Yamazaki, H
-
Journal Title
Biochem.Pharmacol 73
Pages: 2020-2026
Description
「研究成果報告書概要(欧文)」より
-
[Journal Article] Effect of genetic variants of the human flavin-containing monooxygenase 3(FMO3) on N- and S-oxygenation activities2007
Author(s)
Shimizu, M., Yano, H., Nagashima, S., Murayama, N., Zhang, J., Cashman, J.R. Yamazaki, H
-
Journal Title
Drug Metab.Dispos 35
Pages: 328-330
Description
「研究成果報告書概要(欧文)」より
-
-
[Journal Article] Disparity in holo/apoprotein ratios of different standards used for immunoquantification of hepatic cytochrome P450 enzymes2007
Author(s)
Perrett, H., F., Barter, Z.E., Jones, B.C., Yamazaki. H., Tucker, G.T., Rostami-Hodjegan, A
-
Journal Title
Drug Metab.Dispos 35
Pages: 1733-1736
Description
「研究成果報告書概要(欧文)」より
-
-
[Journal Article] Molecular evolution and balancing selection in the flavin-containing monooxygenase 3 gene(FMO3)2007
Author(s)
Allerston, C.K., Shimizu, M., Fujieda, M., Shephard, E.A., Yamazaki, H., Phillips, I.R
-
Journal Title
Pharmacogenet.Genomics 17
Pages: 827-839
Description
「研究成果報告書概要(欧文)」より
-
-
[Journal Article] Different mechanisms for inhibition of human cytochromes P450 1A1, 1A2, and 1B1 by polycyclic aromatic inhibitors.2007
Author(s)
Shimada, T., Murayama, N., Okuda, K., Funae, Y., Yamazaki, H., Guengerich, F.P
-
Journal Title
Chem.Res.Toxicol 20
Pages: 489-496
Description
「研究成果報告書概要(欧文)」より
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-
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[Journal Article] CYP2A13 expressed in human bladder metabolically activates 4-aminobiphenyl2006
Author(s)
Nakajima, M., Itoh, M., Sakai, H., Fukami, T., Katoh, M., Yamazaki, H., Kadlubar, F.F., Imaoka, S., Funae, Y. and Yokoi, T
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Journal Title
Int.J.Cancer 117
Pages: 2020-2026
Description
「研究成果報告書概要(和文)」より
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[Book] 南江堂2007
Author(s)
山崎 浩史, 横井 毅
Total Pages
422
Publisher
製剤学改訂第5版
Description
「研究成果報告書概要(和文)」より
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[Book] 中山書店2007
Author(s)
山崎 浩史
Publisher
毒性物質の生体内運命「最新毒性病理学」
Description
「研究成果報告書概要(和文)」より
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[Book] 臨床薬理研究進行財団2007
Author(s)
山崎 浩史, 清水 万紀子, 永島 里美, 村山 典恵
Publisher
薬物代謝酵素フラビン含有モノオキシゲナーゼがもたらすアミン化合物酸化的代謝の個人差に関する臨床薬理学研究「臨床薬理の進歩No.29」
Description
「研究成果報告書概要(和文)」より
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[Book] 日本医療薬学会会報2007
Author(s)
山崎 浩史
Total Pages
93
Publisher
薬物治療の最適化とバイオマーカーの利用
Description
「研究成果報告書概要(和文)」より
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[Book] 中毒研究2006
Author(s)
山崎 浩史
Total Pages
6
Publisher
臨床中毒とゲノミクス
Description
「研究成果報告書概要(和文)」より
