Evaluation of Circadian Rhythm Disturbances in Mice Models with Impaired Heme Biosynthesis Induced by Environmental Chemicals

环境化学物质引起血红素生物合成受损的小鼠模型昼夜节律紊乱的评估

• 批准号: 18590119
• 负责人: MITSUMOTO Atsushi
• 金额: $ 2.68万
• 依托单位: Josai International University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2009
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590119/
• 关键词: 概日リズム; 生物時計; ポルフィリン症; ヘム; 環境化学物質; 肝障害; グリセオフルビン; 疾病モデル動物; 環境衛生学

We have developed a mouse model of hepatic porphyria induced by ingestion of a chemical substance, griseofulvin (GF), and analyzed the characterization of biochemical and behavioral phenotypes of the porphyria model mice. The porphyria mice exhibited tremendous accumulation of aminolevurinic acid (ALA) and porphyrins asn heme precursors, and also had symptoms, such as liver injury and skin inflammation. In addition, they exhibited several neurological and psychological behaviors, such as anxiety and depression, typically observed in acute porphyria. Moreover, we found that these mice had differential sensitivities to psychological drugs, such as diazepam, comparing to the control mice, without any difference in the pharmacokinetics. Furthermore, circadian activity and temperature rhythms of these mice exhibited phase-advances by a few hours. The abnormal circadian rhythms were ameliorated by the treatment of heme. In conclusion, we demonstrated heme-regulated abnormality of circadian rhythms in the mice model of hepatic porphyria induced by GF.

我们建立了摄入化学物质灰黄霉素（GF）诱导的肝卟啉症小鼠模型，并分析了卟啉症模型小鼠的生化和行为表型特征。卟啉症小鼠表现出氨基乙酰尿酸（ALA）和卟啉 asn 血红素前体的大量积累，并且还出现肝损伤和皮肤炎症等症状。此外，他们还表现出几种神经和心理行为，例如焦虑和抑郁，通常在急性卟啉症中观察到。此外，我们发现与对照小鼠相比，这些小鼠对心理药物（例如地西泮）具有不同的敏感性，但药代动力学没有任何差异。此外，这些小鼠的昼夜节律活动和体温节律表现出相位提前几个小时。血红素治疗改善了异常的昼夜节律。总之，我们在 GF 诱导的肝卟啉症小鼠模型中证实了血红素调节的昼夜节律异常。

项目成果

ポルフィリン症モデルマウスにおける行動異常

卟啉症模型小鼠的行为异常

• 发表时间: 2007
• 作者: 佐藤 陽子;河合 洋;光本 篤史
• 通讯作者: 光本 篤史

Pathophysiologic characterization in Griseofulvin-induced porphyria mice.

灰黄霉素诱导的卟啉症小鼠的病理生理学特征。

• 发表时间: 2007
• 作者: Yoko Satoh;Hiroshi Kawai;Atsushi Mitsumoto
• 通讯作者: Atsushi Mitsumoto

ヘム代謝異常マウスにおける概日リズム障害

血红素代谢紊乱小鼠昼夜节律紊乱

• 发表时间: 2009
• 作者: 岩舘怜子;佐藤陽子;石橋拓也;河合洋;増野匡彦;光本篤史
• 通讯作者: 光本篤史

Efficacy of urine bile acid as a non-invasive indicator of liver damage in rats

• DOI: 10.2131/jts.34.27
• 发表时间: 2009-02-01
• 期刊: JOURNAL OF TOXICOLOGICAL SCIENCES
• 影响因子: 2
• 作者: Kawai, Hiroshi;Kudo, Naomi;Mitsumoto, Atsushi
• 通讯作者: Mitsumoto, Atsushi

Differential Response of Hepatic Porphyria Mice to Administration of Diazepam.

肝卟啉症小鼠对地西泮给药的差异反应。

• 发表时间: 2008
• 作者: Atsushi MITSUMOTO;Yukino WATANABE;Hiroshi KAWAI
• 通讯作者: Hiroshi KAWAI