Systems toxicology: Integrated genomic, proteomic and metabonomic analysis of methapyrilene induced hepatotoxicity in the rat
Systems toxicology: Integrated genomic, proteomic and metabonomic analysis of methapyrilene induced hepatotoxicity in the rat
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DOI：
10.1021/pr0503376
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发表时间：
2006-07-07
影响因子：
4.4
通讯作者：
Nicholson, Jeremy
中科院分区：
文献类型：
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作者：
Craig, Andrew;Sidaway, James;Nicholson, Jeremy
给予大鼠高剂量组胺拮抗剂methapyrilene导致门静脉周围肝坏死。毒性的机制是不明确的，在这里，我们已经利用了一个综合系统的方法来理解的毒性机制相结合的蛋白质组学，代谢组学的H-1 NMR光谱和基因组学的微阵列基因表达谱。以150 mg/kg/天（足以诱导肝坏死）或50 mg/kg/天的亚毒性剂量对雄性大鼠给予methapyrilene 3天。每天收集24小时的尿液，在末次给药后2小时采集血液和肝组织。由此产生的数据进一步定义了在methapyrilene肝毒性过程中信号转导和代谢途径发生的变化，揭示了与氧化应激相关的基因和蛋白质表达水平的改变以及反映在基因/蛋白质表达模式和代谢物中的能量使用变化。被认为是组合和解释多组数据的困难。
Administration of high doses of the histamine antagonist methapyrilene to rats causes periportal liver necrosis. The mechanism of toxicity is ill-defined and here we have utilized an integrated systems approach to understanding the toxic mechanisms by combining proteomics, metabonomics by H-1 NMR spectroscopy and genomics by microarray gene expression profiling. Male rats were dosed with methapyrilene for 3 days at 150 mg/kg/day, which was sufficient to induce liver necrosis, or a subtoxic dose of 50 mg/kg/day. Urine was collected over 24 h each day, while blood and liver tissues were obtained at 2 h after the final dose. The resulting data further define the changes that occur in signal transduction and metabolic pathways during methapyrilene hepatotoxicity, revealing modification of expression levels of genes and proteins associated with oxidative stress and a change in energy usage that is reflected in both gene/protein expression patterns and metabolites. The difficulties of combining and interpreting multiomic data are considered.