Predictive toxicogenomics approaches reveal underlying molecular mechanisms of nongenotoxic carcinogenicity
Predictive toxicogenomics approaches reveal underlying molecular mechanisms of nongenotoxic carcinogenicity
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DOI：
10.1002/mc.20205
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发表时间：
2006-12-01
影响因子：
4.6
通讯作者：
Lord, Peter G.
中科院分区：
文献类型：
--
作者：
Nie, Alex Y.;McMillian, Michael;Lord, Peter G.
毒理基因组学技术定义了毒性基因表达特征，为早期预测和机制研究提供假设，是评价候选药物毒性的重要手段。一个大型的基因表达数据库，建立了cDNA微阵列和肝脏样本处理超过一百范式化合物被挖掘，以确定非遗传毒性致癌物（NGTC）的基因表达特征。从处理24 h的雄性大鼠中获得数据。训练/测试集的24 NGTC和28非致癌物被用来选择基因。一个半穷举，非冗余基因选择算法产生了六个基因（核转运因子2，NUTF 2;孕酮受体膜成分1，Pgrmc 1;肝尿苷二磷酸葡萄糖醛酸转移酶，苯巴比妥诱导型，UDPGTr 2;金属硫蛋白1A，MT 1A; lin-12同源物抑制因子，Sel 1h;和甲硫氨酸腺苷转移酶1，α，Mat 1a），其鉴定NGTC，通过交叉验证估计预测准确率为88.5%。当样品与市售的基于CodeLink寡核苷酸的微阵列杂交时，这六个基因签名集也以84%的准确度预测NGTC。为了揭示非遗传毒性致癌的分子机制，通过Student 'st-test筛选出125个差异表达基因（P < 0.01）。这些基因似乎具有生物学相关性，在这125个基因中的71个注释良好的基因中，有62个在5个生化通路网络中过度表达（大多数与癌症相关），所有这些网络都由一个基因c-myc连接。早期时间点的基因表达谱准确预测化合物的NGTC潜力，并且可以有效地挖掘相同的数据用于其他毒性特征。预测基因证实了先前的工作，并提出了对癌发生早期至关重要的途径。(c)2006威利-利斯公司
Toxicogenomics technology defines toxicity gene expression signatures for early predictions and hypotheses generation for mechanistic studies, which are important approaches for evaluating toxicity of drug candidate compounds. A large gene expression database built using cDNA microarrays and liver samples treated with over one hundred paradigm compounds was mined to determine gene expression signatures for nongenotoxic carcinogens (NGTCs). Data were obtained from male rats treated for 24 h. Training/testing sets of 24 NGTCs and 28 noncarcinogens were used to select genes. A semiexhaustive, nonredundant gene selection algorithm yielded six genes (nuclear transport factor 2, NUTF2; progesterone receptor membrane component 1, Pgrmc1; liver uridine cliphosphate glucuronyltransferase, phenobarbital-inducible form, UDPGTr2; metallothionein 1A, MT1A; suppressor of lin-12 homolog, Sel1h; and methionine adenosyltransferase 1, alpha, Mat1a), which identified NGTCs with 88.5% prediction accuracy estimated by cross-validation. This six genes signature set also predicted NGTCs with 84% accuracy when samples were hybridized to commercially available CodeLink oligo-based microarrays. To unveil molecular mechanisms of nongenotoxic carcinogenesis, 125 differentially expressed genes (P < 0.01) were selected by Student's t-test. These genes appear biologically relevant, of 71 well-annotated genes from these 125 genes, 62 were over-represented in five biochemical pathway networks (most linked to cancer), and all of these networks were linked by one gene, c-myc. Gene expression profiling at early time points accurately predicts NGTC potential of compounds, and the same data can be mined effectively for other toxicity signatures. Predictive genes confirm prior work and suggest pathways critical for early stages of carcinogenesis. (c) 2006 Wiley-Liss, Inc.