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Basic Research for Individualized Medicine

个体化医学基础研究

基本信息

批准号：
15209005
负责人：
KAMATAKI Tetsuya
金额：
$ 28.79万
依托单位：
Hokkaido University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15209005/
关键词：
individualized medicine genetic polymorphism individual variation cytochrome P450 CYP2A6 anti cancer drug whole gene deletion drug oxidation P450 CYP1A2 カフェイン NAT2 個別化医療オーダーメイド

项目摘要

Cytochrome P450 2A6 (CYP2A6) is involved in the metabolism of several kinds of anti cancer drugs, including tegafur, fadrozole and letrozole. Notably, the expression levels of CYP2A6 and its catalytic activities in humans show wide inter-individual variation. One of the causes of this variation has been thought to be the genetic polymorphisms of the CYP2A6. However, this variation could not be fully explained by reported polymorphisms. Therefore, we investigated the CYP2A6 gene of 49 Japanese and 28 Caucasian samples. We identified 45 novel genetic polymorphisms from these samples. We clarified that CYP2A6^*9, which contains SNP in the 5'-flanking region of the CYP2A6 gene, reduced the expression of mRNA and protein, leading to reduction of the enzymatic activities of CYP2A6. We investigate the function of mutant CYP2A6 caused by newly identified SNP using E. coli expression system and human liver microsomes. Coumarin 7-hydroxylase activities of CYP2A6.15 (Lys194Glu) and CYP2A6.16 (Arg203Ser) were lower than that of wild-type CYP2A6. Coumarin 7-hydroxylase activities of liver microsomes with CYP2A6^*15 or CYP2A6^*16 alleles were lower than that with CYP2A6^*1 alleles. These variant alleles were thought to be one of the causes of inter-individual variation of CYP2A6 activity.

细胞色素P450 2A6参与替加氟、法洛唑、来曲唑等多种抗癌药物的代谢。值得注意的是，在人类中，CYP2A6的表达水平及其催化活性表现出很大的个体间差异。这种变异的原因之一被认为是CYP2A6的遗传多态。然而，这种变异不能用已报道的多态来完全解释。因此，我们对49例日本人和28例高加索人的CYP2A6基因进行了研究。我们从这些样本中发现了45个新的遗传多态。我们阐明了在CYP2A6基因5‘侧翼区含有SNP的CYP2A6^*9降低了其mRNA和蛋白的表达，导致了酶活性的降低。我们利用大肠杆菌表达系统和人肝微粒体研究了由新发现的SNP引起的突变型CYP2A6的功能。CYP2A6.15(Lys194Glu)和CYP2A6.16(Arg203Ser)的香豆素7-羟基酶活性低于野生型。携带CYP2A6^*15或CYP2A6^*16等位基因的肝微粒体的香豆素7-羟基酶活性低于携带CYP2A6^*1等位基因的肝微粒体。这些变异等位基因被认为是导致CYP2A6活性个体间差异的原因之一。

项目成果

期刊论文数量（181）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Establishment of ten strains of genetically engineered Salmonella typhimurium TA1538 each co-expressing a form of human cytochrome P450 with NADPH-cytochrome P450 reductase sensitive to various promutagens.

DOI：
10.1016/j.mrgentox.2004.06.003
发表时间：
2004-08
期刊：
Mutation research
影响因子：
0
作者：
Y. Yamazaki;Ken-Ichi Fujita;K. Nakayama;A. Suzuki;Katsunori Nakamura;H. Yamazaki;T. Kamataki
通讯作者：
Y. Yamazaki;Ken-Ichi Fujita;K. Nakayama;A. Suzuki;Katsunori Nakamura;H. Yamazaki;T. Kamataki

Identification of a novel polymorphic enhancer of the human CYP3A4 gene

DOI：
10.1124/mol.65.2.326
发表时间：
2004-02-01
期刊：
MOLECULAR PHARMACOLOGY
影响因子：
3.6
作者：
Matsumura, K;Saito, T;Kamataki, T
通讯作者：
Kamataki, T

Pretreatment with 8-methoxypsoralen, a potent human CYP2A6 inhibitor, strongly inhibits lung tumorigenesis induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in female A/J mice.

DOI：
发表时间：
2003-11
期刊：
Cancer research
影响因子：
11.2
作者：
Hijiri Takeuchi;K. Saoo;M. Yokohira;M. Ikeda;H. Maeta;Masafumi Miyazaki;H. Yamazaki;T. Kamataki;K. Imaida
通讯作者：
Hijiri Takeuchi;K. Saoo;M. Yokohira;M. Ikeda;H. Maeta;Masafumi Miyazaki;H. Yamazaki;T. Kamataki;K. Imaida

Reply : Aryl hydrocarbon hydroxylase represents CYP1B1, and not CYP1A1, in human freshly isolated white cells : trimodal distribution of Japanese population according to induction of CYP1B1 mRNA by environmental dioxins.

答复：在人类新鲜分离的白细胞中，芳基烃羟化酶代表 CYP1B1，而不是 CYP1A1：根据环境二恶英对 CYP1B1 mRNA 的诱导，日本人群的三峰分布。