Developmental study for effective high-through-put screening system for new drug registration

新药注册高效高通量筛选系统的开发研究

基本信息

批准号：
11557175
负责人：
KAMATAKI Tetsuya
金额：
$ 5.25万
依托单位：
HOKKAIDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11557175/
关键词：
P450 HIGH THROUGH PUT PLATE READER INHIBITION DRUG METANBOISM DRUG INTERACTION RECOMBINANT DRUG DEVELOPMENT ハイスループットシステムチトクロームP450 CYP3A4 大腸菌発現系チトクロームb_5 薬物間相互作用水溶性ポリマー

项目摘要

The role of human cytochrome P450 (CYP) in the metabolic activation of N-alkylnitrosamines was examined by Ames test using genetically engineered Salmonella typhimurium (S. typhimurium)YG7108 cells expressing each form of human CYP together with human NADPH-cytochrome P450 reductase (OR). The relationship between the structure of N-alkylnitrosamines and CYP form(s) involved in the activation was evaluated. Eleven strains of S. typhimurium YG7108 cells expressing each form of CYP (CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 or CYP3A5) were employed. Eight N-alkylnitrosamines These N-alkylnitrosamines were mainly activated by CYP2E1, CYP2A6 and CYP1A1. N-alkylnitrosamines with relatively short alkyl chains such as NDMA and NMEA were primarily activated by CYP2E1 as judged by mutagen-producing capacity. With the increase of the number of the carbon atoms of the alkyl chains, the contribution of CYP2A6 increased. CYP2A6 played major roles in the activation of NDEA, NDPA, NMPA, NMBA and NEBA. Interestingly, CYP1A1 became a molecular form of CYP playing a major role in the metabolic activation of NDBA.

人类细胞色素p450（CYP）在N-烷基硝基胺代谢激活中的作用通过AMES测试使用基因工程性的Typhimurium（S. typhimurium）YG7108细胞与人NADPH-CYTOCHROME P450 REDUCTASE（OR）一起表达人NADPH-Cyth-Cyth-cythimurium（S. typhimurium）YG7108细胞。评估了激活中涉及的N-烷基硝基胺的结构与CYP形式之间的关系。表达每种形式的CYP（CYP1A1，CYP1A2，CYP1B1，CYP2A6，CYP2C8，CYP2C9，CYP2C9，CYP2C19，CYP2D6，CYP2D6，CYP2E1，CYP2E1，CYP3A4或CYP3A4或CYP3A4）的11种鼠伤寒himurium YG7108菌株YG7108菌株。这些N-烷基硝基胺这些N-烷基硝胺主要被CYP2E1，CYP2A6和CYP1A1激活。具有相对较短的烷基链（如NDMA和NMEA）的N-烷基硝基胺主要被CYP2E1激活，这是通过产生诱变的能力来判断的。随着烷基链碳原子数量的增加，CYP2A6的贡献增加了。 CYP2A6在NDEA，NDPA，NMPA，NMBA和NEBA的激活中扮演着重要角色。有趣的是，CYP1A1成为CYP的一种分子形式，在NDBA代谢激活中起着重要作用。

项目成果

期刊论文数量（104）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Ken-ichi Fujita, Kazuo Nakayama, Yoshiyuki Yamazaki, Kazuhiro Tsuruma, Masami Yamada, Takehiko Nohmi, Tetsuya Kamataki: "Construction of Salmonella typphimurium YG7108 stains each co-expressing a form of human cytochrome P450 with NADPH-cytochrime P450 re

Ken-ichi Fujita、Kazuo Nakayama、Yoshiyuki Yamazaki、Kazuhiro Tsuruma、Masami Yamada、Takehiko Nohmi、Tetsuya Kamataki：“构建鼠伤寒沙门氏菌 YG7108 染色剂，每种染色剂与 NADPH-细胞色素 P450 共表达一种形式的人细胞色素 P450