Toxicogenomics of bromobenzene hepatotoxicity: a combined transcriptomics and proteomics approach
Toxicogenomics of bromobenzene hepatotoxicity: a combined transcriptomics and proteomics approach
复制标题
DOI：
10.1016/s0006-2952(02)01613-1
复制
发表时间：
2003-03-01
影响因子：
5.8
通讯作者：
van Ommen, B
中科院分区：
文献类型：
--
作者：
Heijne, WHM;Stierum, RH;van Ommen, B
毒理基因组学是一种将传统毒理学研究方法与转录组学、蛋白质组学相结合的新方法。分子水平的影响与生物体的病理生理变化有关，从而能够详细比较机制，并及早发现和预测毒性。本报告讨论了转录组学和蛋白质组学技术在毒理学中的联合使用的价值。溴苯给药在大鼠中诱导急性肝毒性，给药后24小时，导致谷胱甘肽水平耗尽和平均体重降低。这些生理症状与肝脏mRNA和蛋白质含量的许多变化相一致。基因诱导证实了谷胱甘肽-S-转移酶同工酶和环氧化物水解酶参与溴苯代谢，并确定了许多基因可能与溴苯毒性有关。所观察到的谷胱甘肽耗竭与谷胱甘肽生物合成中的关键酶γ-谷氨酰半胱氨酸合成酶的诱导相一致。氧化应激明显从血红素加氧酶，peroxiredoxin I和其他基因的强烈上调。溴苯诱导的蛋白质降解，建议从二维凝胶电泳，上调mRNA水平的蛋白酶体亚基和溶酶体组织蛋白酶L，而基因上调与蛋白质合成的作用。蛋白质和基因表达谱从治疗大鼠明显不同于控制所示的主成分分析，和几个蛋白质发现溴苯治疗后显着变化，通过质谱法进行了鉴定。蛋白质组学和转录组学的研究结果有一定的重叠，这表明转录组学和蛋白质组学技术是互补的，为分子毒理学研究提供了新的可能性。(C)2002年爱思唯尔科技有限公司All rights reserved.
Toxicogenomics is a novel approach integrating the expression analysis of thousands of genes (transcriptomics) or proteins (proteomics) with classical methods in toxicology. Effects at the molecular level are related to pathophysiological changes of the organisms, enabling detailed comparison of mechanisms and early detection and prediction of toxicity. This report addresses the value of the combined use of transcriptomics and proteomics technologies in toxicology. Acute hepatotoxicity was induced in rats by bromobenzene administration resulting in depleted glutathione levels and reduced average body weights, 24 hr after dosage. These physiological symptoms coincided with many changes of hepatic mRNA and protein content. Gene induction confirmed involvement of glutathione-S-transferase isozymes and epoxide hydrolase in bromobenzene metabolism and identified many genes possibly relevant in bromobenzene toxicity. Observed glutathione depletion coincided with induction of the key enzyme in glutathione biosynthesis, gamma-glutamylcysteine synthetase. Oxidative stress was apparent from strong upregulation of heme oxygenase, peroxiredoxin I and other genes. Bromobenzene-induced protein degradation was suggested from two-dimensional gel electrophoresis, upregulated mRNA levels for proteasome subunits and lysosomal cathepsin L, whereas also genes were upregulated with a role in protein synthesis. Both protein and gene expression profiles from treated rats were clearly distinct from controls as shown by principal component analysis, and several proteins found to significantly change upon bromobenzene treatment were identified by mass spectrometry. A modest overlap in results from proteomics and transcriptomics was found. This work indicates that transcriptomics and proteomics technologies are complementary to each other and provide new possibilities in molecular toxicology. (C) 2002 Elsevier Science Inc. All rights reserved.