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首页> 外文期刊>Archives of Toxicology >Characterisation of the NRF2 transcriptional network and its response to chemical insult in primary human hepatocytes: implications for prediction of drug-induced liver injury
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Characterisation of the NRF2 transcriptional network and its response to chemical insult in primary human hepatocytes: implications for prediction of drug-induced liver injury

机译：NRF2转录网络的表征及其对原发性肝细胞化学损害的反应：对药物诱导肝损伤预测的影响

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摘要

The transcription factor NRF2, governed by its repressor KEAP1, protects cells against oxidative stress. There is interest in modelling the NRF2 response to improve the prediction of clinical toxicities such as drug-induced liver injury (DILI). However, very little is known about the makeup of the NRF2 transcriptional network and its response to chemical perturbation in primary human hepatocytes (PHH), which are often used as a translational model for investigating DILI. Here, microarray analysis identified 108 transcripts (including several putative novel NRF2-regulated genes) that were both downregulated by siRNA targeting NRF2 and upregulated by siRNA targeting KEAP1 in PHH. Applying weighted gene co-expression network analysis (WGCNA) to transcriptomic data from the Open TG-GATES toxicogenomics repository (representing PHH exposed to 158 compounds) revealed four co-expressed gene sets or modules' enriched for these and other NRF2-associated genes. By classifying the 158 TG-GATES compounds based on published evidence, and employing the four modules as network perturbation metrics, we found that the activation of NRF2 is a very good indicator of the intrinsic biochemical reactivity of a compound (i.e. its propensity to cause direct chemical stress), with relatively high sensitivity, specificity, accuracy and positive/negative predictive values. We also found that NRF2 activation has lower sensitivity for the prediction of clinical DILI risk, although relatively high specificity and positive predictive values indicate that false positive detection rates are likely to be low in this setting. Underpinned by our comprehensive analysis, activation of the NRF2 network is one of several mechanism-based components that can be incorporated into holistic systems toxicology models to improve mechanistic understanding and preclinical prediction of DILI in man.
机译：由其阻遏物Keap1控制的转录因子NRF2保护细胞免受氧化应激。有兴趣建模NRF2响应，以改善药物诱导肝损伤等临床毒性（DILI）的预测。然而，关于NRF2转录网络的化妆很少，并且其对原发性人肝细胞（PHH）的化学扰动的响应，其通常用作研究DiLi的翻译模型。这里，微阵列分析鉴定了通过靶向NRF2的siRNA下调的108转录物（包括几项推定的新型NRF2-调节基因），并通过靶向Keap1以pHH靶向keap1来上调。将加权基因共表达网络分析（WGCNA）应用于来自开放的TG栅极有毒源型储存库的转录组数据（表示暴露于158种化合物的PHH）揭示了四种共同表达的基因组或富含这些和其他NRF2相关基因的组成基因组或模块。通过基于已发表的证据对158 TG-Gates化合物进行分类，并使用四个模块作为网络扰动指标，我们发现NRF2的激活是化合物的内在生化反应性的非常好的指标（即其引起直接的倾向化学胁迫），具有相对高的灵敏度，特异性，准确度和正/负预测值。我们还发现NRF2激活具有较低的灵敏度对临床帝力风险的预测，尽管相对较高的特异性和阳性预测值表明该设置中的假阳性检测率可能处于低位。通过我们的综合分析为基础，NRF2网络的激活是可以纳入整体系统毒理学模型的几种基于机制的组件之一，以提高人类帝力的机械理解和临床前预测。

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  • 来源
    《Archives of Toxicology》 |2019年第2期|共15页
  • 作者

    Copple Ian M.; den Hollander Wouter; Callegaro Giulia; Mutter Fiona E.; Maggs James L.; Schofield Amy L.; Rainbow Lucille; Fang Yongxiang; Sutherland Jeffrey J.; Ellis Ewa C.; Ingelman-Sundberg Magnus; Fenwick Stephen W.; Goldring Christopher E.; van de Water Bob; Stevens James L.; Park B. Kevin;

  • 作者单位

    Univ Liverpool Inst Translat Med Dept Mol &

    Clin Pharmacol MRC Ctr Drug Safety Sci Liverpool;

    Leiden Univ Leiden Acad Ctr Drug Res Div Toxicol NL-2333 CC Leiden Netherlands;

    Leiden Univ Leiden Acad Ctr Drug Res Div Toxicol NL-2333 CC Leiden Netherlands;

    Univ Liverpool Inst Translat Med Dept Mol &

    Clin Pharmacol MRC Ctr Drug Safety Sci Liverpool;

    Univ Liverpool Inst Translat Med Dept Mol &

    Clin Pharmacol MRC Ctr Drug Safety Sci Liverpool;

    Univ Liverpool Inst Translat Med Dept Mol &

    Clin Pharmacol MRC Ctr Drug Safety Sci Liverpool;

    Univ Liverpool Inst Integrat Biol Ctr Genom Res Liverpool L69 7ZB Merseyside England;

    Univ Liverpool Inst Integrat Biol Ctr Genom Res Liverpool L69 7ZB Merseyside England;

    Eli Lilly &

    Co Lilly Res Labs Indianapolis IN 46285 USA;

    Karolinska Univ Huddinge Hosp Dept Clin Sci Intervent &

    Technol CLINTEC Liver Cell Lab Unit;

    Karolinska Inst Dept Physiol &

    Pharmacol Sect Pharmacogenet S-17177 Stockholm Sweden;

    Aintree Univ Hosp NHS Fdn Trust Dept Hepatobiliary Surg Liverpool L9 7AL Merseyside England;

    Univ Liverpool Inst Translat Med Dept Mol &

    Clin Pharmacol MRC Ctr Drug Safety Sci Liverpool;

    Leiden Univ Leiden Acad Ctr Drug Res Div Toxicol NL-2333 CC Leiden Netherlands;

    Eli Lilly &

    Co Lilly Res Labs Indianapolis IN 46285 USA;

    Univ Liverpool Inst Translat Med Dept Mol &

    Clin Pharmacol MRC Ctr Drug Safety Sci Liverpool;

  • 收录信息
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 毒物学（毒理学）;
  • 关键词

    DILI; NFE2L2; KEAP1; WGCNA; Oxidative stress;

    机译：D IL i;NF E2l2;K EAP1;WG cn A;oxidative stress;

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