Transcription profiling distinguishes dose-dependent effects in the livers of rats treated with clofibrate
Transcription profiling distinguishes dose-dependent effects in the livers of rats treated with clofibrate
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DOI：
10.1080/01926230390202353
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发表时间：
2003-07-01
影响因子：
1.5
通讯作者：
Curtiss, SW
中科院分区：
文献类型：
--
作者：
Kramer, JA;Blomme, EAG;Curtiss, SW
过氧化物酶体增殖剂（例如贝特类药物）通过过氧化物酶体增殖剂激活受体（PPAR）-α 作为降血脂剂发挥作用。许多过氧化物酶体增殖物也是啮齿类动物的非基因毒性肝癌致癌物和肝毒物。我们使用 cDNA 微阵列对用 3 剂过氧化物酶体增殖剂安妥明治疗 5 天的大鼠肝脏进行转录分析。通过肝脏与体重比、丙氨酸转氨酶 (ALT) 增加和组织病理学检查评估，所有 3 个剂量均具有肝脏影响。对转录谱数据的分析发现了几种机制途径中许多基因表达的变化，这些变化支持了有关过氧化物酶体增殖物介导的致癌性的现有假设。此外，转录谱、组织病理学和临床化学结果表明对安妥明有双相反应。这些发现深入了解了安妥明对啮齿动物的毒性和致癌作用的发病机制，并证明了 cDNA 微阵列能够提供有关药物开发过程中确定的毒性机制的信息。
Peroxisome proliferators such as the fibrates act via the peroxisome proliferator activated receptor (PPAR)-alpha as hypolipidemic agents. Many peroxisome proliferators are also nongenotoxic hepatic carcinogens and hepatotoxicants in rodents. We performed transcription profiling using cDNA microarrays on livers of rats treated for 5 days with 3 doses of the peroxisome proliferator clofibrate. All 3 doses had hepatic effects as assessed by liver to body weight ratio, alanine aminotransferase (ALT) increases and histopathology examination. Analysis of the transcription profiling data identified changes in the expression of many genes within several mechanistic pathways that support existing hypotheses regarding peroxisome proliferator mediated carcinogenicity. Additionally, the transcription profiling, histopathology, and clinical chemistry results suggested a biphasic response to clofibrate. These findings provide insight into the pathogenesis of toxic and carcinogenic effects of clofibrate in rodents and demonstrate the ability of cDNA microarrays to provide information regarding mechanisms of toxicity identified during the drug development process.