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Polymorphism of drug-metabolising enzymes

Polymorphism of drug-metabolising enzymes
药物代谢酶的多态性
批准号:
08672624
负责人:
YASUHARA Hajime
金额:
$1.41万
依托单位:
依托单位国家:
日本
项目类别:
Grant-in-Aid for Scientific Research (C)
财政年份:
1996
资助国家:
日本
项目状态:
已结题
起止时间:
1996 至 1997

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项目成果

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中文摘要
翻译
在本项目中,我们指定了负责甲美二酮代谢的细胞色素P450同工酶,该酶被广泛用于估计人体内肝脏药物代谢能力。为建立简单可靠的酶缺乏症基因分型评价方法,比较了探针药物测定的表型与基因分型的关系。采用人肝微粒体片段和人淋巴母细胞样细胞表达细胞色素P450酶测定甲美二酮代谢。通过这些实验,确定了甲美二酮在人体内主要由CYP2E1酶代谢。另一方面,利用28名健康志愿者,检测5外显子CYP2C19m1和4外显子CYP2C19m2这对突变的基因型与CYP2C19表型之间的关系。28名受试者中有6人外显子4和外显子5的野生型等位基因(wt/wt)为纯合子,11人CYP2C19m1为杂合子(wt/m1);CYP2C19m2杂合子5个(wt/m2);CYP2C19m1纯合子为5个(m1/m1);两个缺陷各有1个杂合子(m1/m2)。纯合子基因型与广泛代谢物(EMs: wt/wt)和pm (m1/m1)的表型一致。然而,杂合基因型与表型不明显相容:11个wt/m1基因型中有1个被判断为PM。wt/m2的5例受试者为EMs。由于奥美拉唑和5-OH奥美拉唑的血清浓度极低,1例m1/m2的表型无法确定。由此可见,CYP2C19基因型和表型在受试者中具有良好的相关性。在杂合型受试者中,CYP2C19基因型与表型之间的关系需要进一步的详细研究。
英文摘要
In this project, we have specified the cytochrome P450 isozyme that responsible to trimethadione metabolism which widely employed for the estimation of hepatic drug-metabolizing capacity in human in vivo. And also to establish the simple and reliable procedure for the evaluate the enzyme deficiency by genotyping procedure, relationship between phenotype determined by employing the probe drug and genotype were compared.Trimethadione metabolism had been determined by employing the human liver microsomal fraction and human lymphoblastoid cell expressed cytochrome P450 enzymes. By these experiments, it had been defined that trimethadione is predominantly metabolyzed by CYP2E1 enzyme in human.On the other hand, relationship between CYP2C19 phenotype and genotype of the couple of mutations, CYP2C19m1 in exon 5 and CYP2C19m2 in exon 4 were determined by using the 28 of phenotyped recruted healthy volunteers. Six out of 28 subjects were homozygous for the wild-type (wt/wt) allele in both exon 4 and exon 5,11 heterozygous for the CYP2C19m1 (wt/m1) ; 5 heterozygous for the CYP2C19m2 (wt/m2) ; 5 homozygous for the CYP2C19m1 (m1/m1) ; 1 heterozygous for both defects (m1/m2). The homozygous genotype was compatible with the phenotype of the extensive metabolizer (EMs : wt/wt) and PMs (m1/m1). The heterozygous genotype, however, was not clearly compatible with the phenotype : one out of 11 with wt/m1 genotype was judged as PM.Five subjects with wt/m2 were EMs. The phenotype of one subject with m1/m2 could not be identified since extremely low serum concentration of omeprazole and 5-OH omeprazole. From these results, genotype and phenotype of CYP2C19 were well correlated among the subjects. Further detail study will be needed to clarify the relationship between the CYP2C19 genotype and phenotype in subjects with a heterozygous genotype.
期刊论文(12)
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会议论文
内田 直樹、安原 一 他: "Omeprazoleを用いたCYP2C19表現型と遺伝子型の関連性に関する検討-表現型検索の簡便化への考察-" 臨床薬理. 29(3)(印刷中). (1998)
Naoki Uchida、Hajime Yasuhara 等人:“使用奥美拉唑研究 CYP2C19 表型和基因型之间的关系 - 简化表型搜索的考虑 -”临床药理学 (Clinical Pharmacology) 29(3)(出版中)。
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通讯作者:
Naoki Uchida, Eiji Uchida, Kunihiko Fukuchi, Takahiko Kouda, Katsuhiko Yoshida, Norimitsu Kurata, Yuki Nishimura, Makoto Watanabe, Yukihiko Shirota, Yasuyo Yamada, Kunihide Gomi and Hajime Yasuhara: Jpn.J.Clin.Pharmacol.Ther.Vol.29(3)(in Japanese)(in pres
Naoki Uchida、Eiji Uchida、Kunihiko Fukuchi、Takahiko Kouda、Katsuhiko Yoshida、Norimitsu Kurata、Yuki Nishimura、Makoto Watanabe、Yukihiko Shirota、Yasuyo Yamada、Kunihide Gomi 和 Hajime Yasuhara:Jpn.J.Clin.Pharmacol.Ther.Vol.29(
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Takahiko Kouda, Eiji Uchida, Ken Shimada, Naoki Uchida, Norimitsu Kurata, Yuki Nishimura, Mariko Iwase, Yoshie Kawamura and Hajime Yasuhara.: "Evaluation hepatic drug-metabolizing capacity using trimethadione as a model drug in elderly subjects." Jpn.J.Cl
Takahiko Kouda、Eiji Uchida、Ken Shimada、Naoki Uchida、Norimitsu Kurata、Yuki Nishimura、Mariko Iwase、Yoshie Kawamura 和 Hajime Yasuhara.:“使用三甲二酮作为老年受试者的模型药物评估肝脏药物代谢能力。”
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通讯作者:
Yuki Nishimura, Norimitsu Kurata, Makoto Watanabe, Eiji Uchida, and Hajime Yasuhara: "Trimethadione N-demethylation by rat liver CYP2E1 in vitro." Res.Commun.Mol.Pathol.Pharmacol.Vol.93. 43-56 (1996)
Yuki Nishimura、Norimitsu Kurata、Makoto Watanabe、Eiji Uchida 和 Hajime Yasuhara:“体外大鼠肝脏 CYP2E1 引起的三甲二酮 N-去甲基化”。
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共 10 条
    Association between genetic polymorphisms of drug-metabolizingenzymes and factors of liver cancer
    • 批准号:
      22501059
    • 项目类别:
      Grant-in-Aid for Scientific Research (C)
    • 资助金额:
      $2.66万
    • 财政年份:
      2010
    • 负责人:
      YASUHARA Hajime
    • 依托单位:
    Evaluation of Drug-metabolizing enzyme activity and-drug interaction in paitients with hepatic disease
    • 批准号:
      12672224
    • 项目类别:
      Grant-in-Aid for Scientific Research (C)
    • 资助金额:
      $1.92万
    • 财政年份:
      2000
    • 负责人:
      YASUHARA Hajime
    • 依托单位:
    Study of the effects of antineoplastic agents on drug metabolizing enzymes and evaluation of its efficacy and safety
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      10672157
    • 项目类别:
      Grant-in-Aid for Scientific Research (C)
    • 资助金额:
      $2.05万
    • 财政年份:
      1998
    • 负责人:
      YASUHARA Hajime
    • 依托单位:
    Polymorphism of drug-metabolyzing enzymes and the assessment of drug efficacy and safety
    • 批准号:
      06672277
    • 项目类别:
      Grant-in-Aid for General Scientific Research (C)
    • 资助金额:
      $1.34万
    • 财政年份:
      1994
    • 负责人:
      YASUHARA Hajime
    • 依托单位:
    国内基金
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    • 批准号:
      82104297
    • 项目类别:
      青年科学基金项目(C类)
    • 资助金额:
      30.0万元
    • 批准年份:
      2021
    • 负责人:
      徐仁爱
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    CYP2C19抑制内质网应激缓解心肌缺血再灌注损伤的机制研究
    • 批准号:
      82172168
    • 项目类别:
      面上项目
    • 资助金额:
      54万元
    • 批准年份:
      2021
    • 负责人:
      侯旭敏
    • 依托单位:
    基于多源影像及分子特征关联的CYP2C19基因多态性分类在辅助急性上消化道出血用药的应用研究
    • 批准号:
      62176168
    • 项目类别:
      面上项目
    • 资助金额:
      57万元
    • 批准年份:
      2021
    • 负责人:
      金木兰
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    circRNA29254—miR-29a-3p—CYP2C19轴在脑梗死氯吡格雷抵抗中的作用及机制
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      82171295
    • 项目类别:
      面上项目
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      54万元
    • 批准年份:
      2021
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      杨杰
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