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p53 Contributes to Differentiating Gene Expression Following Exposure to Acetaminophen and Its Less Hepatotoxic Regioisomer Both In Vitro and In Vivo

机译:p53有助于在暴露于对乙酰氨基酚及其肝脏毒性较低的区域异构体后体外和体内差异化基因表达。

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摘要

The goal of the present study was to compare hepatic toxicogenomic signatures across in vitro and in vivo mouse models following exposure to acetaminophen (APAP) or its relatively nontoxic regioisomer 3′-hydroxyacetanilide (AMAP). Two different Affymetrix microarray platforms and one Agilent Oligonucleotide microarray were utilized. APAP and AMAP treatments resulted in significant and large changes in gene expression that were quite disparate, and likely related to their different toxicologic profiles. Ten transcripts, all of which have been implicated in p53 signaling, were identified as differentially regulated at all time-points following APAP and AMAP treatments across multiple microarray platforms. Protein-level quantification of p53 activity aligned with results from the transcriptomic analysis, thus supporting the implicated mechanism of APAP-induced toxicity. Therefore, the results of this study provide good evidence that APAP-induced p53 phosphorylation and an altered p53-driven transcriptional response are fundamental steps in APAP-induced toxicity.
机译:本研究的目的是比较暴露于对乙酰氨基酚(APAP)或其相对无毒的区域异构体3'-羟基乙酰苯胺(AMAP)后在体外和体内小鼠模型中的肝毒性基因组学特征。使用了两个不同的Affymetrix微阵列平台和一个安捷伦寡核苷酸微阵列。 APAP和AMAP处理导致基因表达的显着和大变化,这些变化完全不同,并且可能与它们的不同毒理学特征有关。在跨多个微阵列平台进行APAP和AMAP处理后,在所有时间点都鉴定出十个转录物,所有这些转录物均与p53信号传导有关。 p53活性的蛋白质水平定量与转录组学分析的结果一致,从而支持了APAP诱导的毒性的相关机制。因此,这项研究的结果提供了很好的证据,表明APAP诱导的p53磷酸化和p53驱动的转录反应的改变是APAP诱导的毒性的基本步骤。

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