Expression profiling of acetaminophen liver toxicity in mice using microarray technology
Expression profiling of acetaminophen liver toxicity in mice using microarray technology
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DOI：
10.1006/bbrc.2001.4576
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发表时间：
2001-03-23
影响因子：
3.1
通讯作者：
Pohl, LR
中科院分区：
文献类型：
--
作者：
Reilly, TP;Bourdi, M;Pohl, LR
药物性肝毒性导致严重的发病率和死亡率，是药物开发中的一个主要问题，这在很大程度上是由于对药物性肝损伤的机制(S)缺乏了解。为了解决这个问题，我们使用能够确定11000个基因的表达谱和表达序列标签(EST)的高密度寡核苷酸微阵列，评估了肝毒性剂量的对乙酰氨基酚(APAP)治疗的小鼠肝脏内基因表达的调节，发现APAP治疗的小鼠肝脏内的基因表达发生了显著的变化，无论是阳性还是阴性。APAP诱导的毒性影响到肝脏生理的许多方面，例如，导致生长停滞和细胞周期调节蛋白、应激诱导蛋白、转录因子LRG-21、细胞因子信号转导抑制物(SOCS)-2蛋白和纤溶酶原激活物抑制物-1(PAI-1)的基因表达增加两倍，其中许多这些基因和EST只有在APAP治疗后才能在肝脏内检测到，这表明它们在促进或防止进一步毒性方面具有潜在的重要性。这些数据为机制研究提供了新的方向，可能会导致更好地理解药物诱导的肝损伤的分子基础，并最终更合理地设计更安全的药物。(C)2001年学术出版社。
Drug-induced hepatotoxicity causes significant morbidity and mortality and is a major concern in drug development, This is due, in large part, to insufficient knowledge of the mechanism(s) of drug-induced liver injury. In order to address this problem, we have evaluated the modulation of gene expression within the livers of mice treated with a hepatotoxic dose of acetaminophen (APAP) using high-density oligonucleotide microarrays capable of determining the expression profile of >11,000 genes and expressed sequence tags (ESTs), Significant alterations in gene expression, both positive and negative, were noted within the livers of APAP-treated mice. APAP-induced toxicity affected numerous aspects of liver physiology causing, for instance, >twofold increased expression of genes that encode for growth arrest and cell cycle regulatory proteins, stress-induced proteins, the transcription factor LRG-21, suppressor of cytokine signaling (SOCS)-2-protein, and plasminogen activator inhibitor-1 (PAI-1), A number of these and other genes and ESTs were detectable within the liver only after APAP treatment suggesting their potential importance in propagating or preventing further toxicity. These data provide new directions for mechanistic studies that may lead to a better understanding of the molecular basis of drug-induced liver injury and, ultimately, to a more rational design of safer drugs. (C) 2001 Academic Press.