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首页> 外文期刊>International Journal of Environmental Research and Public Health >Using Bioinformatic Approaches to Identify Pathways Targeted by Human Leukemogens
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Using Bioinformatic Approaches to Identify Pathways Targeted by Human Leukemogens

机译：使用生物信息学方法识别人类白血病原靶向的途径

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We have applied bioinformatic approaches to identify pathways common to chemical leukemogens and to determine whether leukemogens could be distinguished from non-leukemogenic carcinogens. From all known and probable carcinogens classified by IARC and NTP, we identified 35 carcinogens that were associated with leukemia risk in human studies and 16 non-leukemogenic carcinogens. Using data on gene/protein targets available in the Comparative Toxicogenomics Database (CTD) for 29 of the leukemogens and 11 of the non-leukemogenic carcinogens, we analyzed for enrichment of all 250 human biochemical pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. The top pathways targeted by the leukemogens included metabolism of xenobiotics by cytochrome P450, glutathione metabolism, neurotrophin signaling pathway, apoptosis, MAPK signaling, Toll-like receptor signaling and various cancer pathways. The 29 leukemogens formed 18 distinct clusters comprising 1 to 3 chemicals that did not correlate with known mechanism of action or with structural similarity as determined by 2D Tanimoto coefficients in the PubChem database. Unsupervised clustering and one-class support vector machines, based on the pathway data, were unable to distinguish the 29 leukemogens from 11 non-leukemogenic known and probable IARC carcinogens. However, using two-class random forests to estimate leukemogen and non-leukemogen patterns, we estimated a 76% chance of distinguishing a random leukemogenon-leukemogen pair from each other.
机译：我们已应用生物信息学方法来识别化学性白血病致癌物的常见途径，并确定是否可以将致癌物与非致癌物区别开来。从IARC和NTP分类的所有已知和可能的致癌物中，我们在人体研究中确定了35种与白血病风险相关的致癌物和16种非致白血病的致癌物。使用比较毒物基因组数据库（CTD）中29种白血病致病原和11种非白血病致癌原的基因/蛋白质靶点数据，我们分析了《京都基因与基因组百科全书》（KEGG）中所有250条人类生化途径的富集）数据库。白血病原针对的主要途径包括异源生物通过细胞色素P450代谢，谷胱甘肽代谢，神经营养蛋白信号传导途径，细胞凋亡，MAPK信号传导，Toll样受体信号传导和各种癌症途径。这29种白血病原形成了18种不同的簇，包含1-3种化学物质，这些化学物质与已知作用机理或结构相似性均不相关，而这些相似性由PubChem数据库中的2D Tanimoto系数确定。基于路径数据，无监督聚类和一类支持向量机无法将29种白血病原与11种非白血病原已知和可能的IARC致癌物区分开。但是，使用两类随机森林来估计致白血病和非致白血病的模式，我们估计有76％的机会将随机的致白血病/非致白血病的对彼此区分开。

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