Predose and Postdose Blood Gene Expression Profiles Identify the Individuals Susceptible to Acetaminophen-Induced Liver Injury in Rats.
Predose and Postdose Blood Gene Expression Profiles Identify the Individuals Susceptible to Acetaminophen-Induced Liver Injury in Rats.
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给药前和给药后血液基因表达谱鉴定易受对乙酰氨基酚诱导的大鼠肝损伤的个体
DOI：
10.1371/journal.pone.0141750
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Gao Y
中科院分区：
文献类型：
--
作者：
Lu X;Hu B;Zheng J;Ji C;Fan X;Gao Y
药物性肝损伤（DILI）的程度在不同个体之间可能差异很大。因此，确定DILI的易感人群至关重要。本研究的目的是确定给药前和给药后大鼠血液的转录组学分析是否允许使用广泛应用的镇痛剂对乙酰氨基酚（APAP）作为模型药物预测DILI易感个体。根据丙氨酸氨基转移酶水平的排名，APAP治疗后将5只最敏感和5只最耐药的大鼠确定为两个亚组。通过微阵列分析确定这些大鼠血液样品的给药前和给药后基因表达谱。在给药前数据中，158个基因的表达在易感大鼠和抗性大鼠中存在先天差异。为了寻找更可靠的药物反应相关生物标志物来检测个体对APAP诱导的肝损伤（AILI）的易感性，检测了APAP治疗后这些基因表达的变化。通过进一步的筛选方法，根据药物治疗前后两个亚组之间的基因表达趋势，确定了10个基因作为区分易感和耐药大鼠的潜在给药前生物标志物。其中，Incense、Rpgrip 1、Sbf 1和Mmp 12四个基因在一组独立动物的实时PCR中可重复。它们在AILI抵抗大鼠中均先天性高表达，与细胞增殖和组织修复功能密切相关。说明药物治疗前细胞增殖和组织修复能力越强的大鼠对AILI的抵抗力越强。在这项研究中，我们证明了给药前和给药后血液中的基因表达谱的组合可以识别药物相关的DILI的个体间变异，这是一种新的和重要的方法来识别易感人群的DILI。
The extent of drug-induced liver injury (DILI) can vary greatly between different individuals. Thus, it is crucial to identify susceptible population to DILI. The aim of this study was to determine whether transcriptomics analysis of predose and postdose rat blood would allow prediction of susceptible individuals to DILI using the widely applied analgesic acetaminophen (APAP) as a model drug. Based on ranking in alanine aminotransferase levels, five most susceptible and five most resistant rats were identified as two sub-groups after APAP treatment. Predose and postdose gene expression profiles of blood samples from these rats were determined by microarray analysis. The expression of 158 genes innately differed in the susceptible rats from the resistant rats in predose data. In order to identify more reliable biomarkers related to drug responses for detecting individuals susceptibility to APAP-induced liver injury (AILI), the changes of these genes' expression posterior to APAP treatment were detected. Through the further screening method based on the trends of gene expression between the two sub-groups before and after drug treatment, 10 genes were identified as potential predose biomarkers to distinguish between the susceptible and resistant rats. Among them, four genes, Incenp, Rpgrip1, Sbf1, and Mmp12, were found to be reproducibly in real-time PCR with an independent set of animals. They were all innately higher expressed in resistant rats to AILI, which are closely related to cell proliferation and tissue repair functions. It indicated that rats with higher ability of cell proliferation and tissue repair prior to drug treatment might be more resistant to AILI. In this study, we demonstrated that combination of predose and postdose gene expression profiles in blood might identify the drug related inter-individual variation in DILI, which is a novel and important methodology for identifying susceptible population to DILI.