Thalidomide increases cytochrome P450 activity and drug metabolism in liver through direct activation of nuclear receptor CAR and PXR

沙利度胺通过直接激活核受体 CAR 和 PXR 增加肝脏细胞色素 P450 活性和药物代谢

• 批准号: 23590200
• 负责人: YAMAZAKI Hiroshi
• 金额: $ 3.49万
• 依托单位: Showa Pharmaceutical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2013
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23590200/
• 关键词: 薬物代謝; サリドマイド; P450 3A4; 酵素誘導; ヒト型薬物代謝; ヒト肝移植キメラマウス; 反応性代謝物; グルタチオン付加体

We demonstrated heterotropic cooperativity of human cytochrome P450 (P450) 3A4/5 by the teratogen thalidomide using a model substrate midazolam in various in vitro and in vivo models. Chimeric mice with humanized liver displayed enhanced midazolam clearance upon pre-treatment with orally administered thalidomide, presumably because of human P450 3A induction. Thalidomide enhanced levels of P450 3A4/2B6 mRNA, protein expression, and/or oxidation activity in human hepatocytes indirectly suggesting activation of gene transcription factors. Thalidomide and its human proportionate metabolite 5-hydroxythalidomide displayed significant modulation of coregulator interaction with CAR and PXR ligand-binding domains similar to established agonists for these receptors. These results collectively suggest that thalidomide could act as a ligand for PXR and CAR and cause enzyme induction. The possibilities of drug interactions during thalidomide therapy in humans should be evaluated further.

我们在各种体外和体内模型中使用模型底物咪达唑仑证明了致畸剂沙利度胺对人细胞色素P450（P450）3A 4/5的异嗜协同性。具有人源化肝脏的嵌合小鼠在口服沙利度胺预处理后显示出增强的咪达唑仑清除，推测是由于人P450 3A诱导。沙利度胺增强人肝细胞中P450 3A 4/2B 6 mRNA水平、蛋白表达和/或氧化活性，间接表明基因转录因子的激活。沙利度胺及其人比例代谢物5-羟基沙利度胺显示出与CAR和PXR配体结合结构域的协同调节相互作用的显著调节，类似于这些受体的已建立的激动剂。这些结果共同表明，沙利度胺可以作为PXR和CAR的配体并引起酶诱导。沙利度胺治疗期间药物相互作用的可能性应进一步评估。

项目成果

Plasma concentrations of melengestrol acetate in humans extrapolated from the pharmacokinetics established in in vivo experiments with rats and chimeric mice with humanized liver and physiologically based pharmacokinetic modeling

根据大鼠和嵌合小鼠体内实验建立的人源化肝脏和基于生理学的药代动力学模型建立的药代动力学推断出醋酸美仑孕酮在人体内的血浆浓度

• DOI: 10.1016/j.yrtph.2013.01.008
• 发表时间: 2013
• 期刊: Regul.Toxicol.Pharmacol
• 作者: Tsukada;A.;Suemizu;H.;Murayama;N.;Takano;R.;Shimizu;M.;Nakamura;M.;and Yamazaki;H
• 通讯作者: H

Acrylonitrile concentrations hypothetically modeled in humans

假设模拟人体丙烯腈浓度

• 发表时间: 2013
• 作者: 竹内裕紀;菊池祐紀子;平野俊彦;岩本整;中村有紀;今野理;城島嘉麿;木原優;横山卓剛;虎石竜典;川口崇;河地茂行;奥山清;畝崎榮;島津元秀;永味千枝,堀英生,菊池千草,竹内正義,松永民秀;Andre Kamkin;Hiroshi Yamazaki
• 通讯作者: Hiroshi Yamazaki

Species, Ethnic, and Individual Differences in Human Drug-metabolizing Cytochrome P450 Enzymes

人类药物代谢细胞色素 P450 酶的物种、民族和个体差异

• 作者: Inoue;H;IIhara;A;Takahashi;H;Shimada;I;Ishida;I and Maeda;Y;Hiroshi Yamazaki
• 通讯作者: Hiroshi Yamazaki

P450 Based DDI and Clinical Significance: Genotyping and Phenotyping

基于 P450 的 DDI 和临床意义：基因分型和表型分析

• 发表时间: 2013
• 作者: グリミル・ムヒタル;竹内裕紀;畝崎榮;平野俊彦;島津元秀;Hiroshi Yamazaki
• 通讯作者: Hiroshi Yamazaki

OLINDAを用いた放射線内部被ばく評価

使用 OLINDA 进行辐射内照射评估

• 发表时间: 2011
• 作者: Kudo T;Hisaka A;Sugiyama Y;Ito K.;永味千枝;山崎浩史
• 通讯作者: 山崎浩史