Werle-Schneider Gisela, Wölfelschneider Andreas, von Brevern Marie Charlotte, Scheel Julia, Storck Thorsten, Müller Dieter, Glöckner Reinhild, Bartsch Helmut, Bartelmann Matthias
Division of Toxicology and Cancer Risk Factors, German Cancer Research Center, (DKFZ), Heidelberg, Germany.
Int J Toxicol. 2006 Sep-Oct;25(5):379-95. doi: 10.1080/10915810600846963.
Transcription profiling is used as an in vivo method for predicting the mode-of-action class of nongenotoxic carcinogens. To set up a reliable in vitro short-term test system DNA microarray technology was combined with rat liver slices. Seven compounds known to act as tumor promoters were selected, which included the enzyme inducers phenobarbital, alpha-hexachlorocyclohexane, and cyproterone acetate; the peroxisome proliferators WY-14,643, dehydroepiandrosterone, and ciprofibrate; and the hormone 17alpha-ethinylestradiol. Rat liver slices were exposed to various concentrations of the compounds for 24 h. Toxicology-focused TOXaminer DNA microarrays containing approximately 1500 genes were used for generating gene expression profiles for each of the test compound. Hierarchical cluster analysis revealed that (i) gene expression profiles generated in rat liver slices in vitro were specific allowing classification of compounds with similar mode of action and (ii) expression profiles of rat liver slices exposed in vitro correlate with those induced after in vivo treatment (reported previously). Enzyme inducers and peroxisome proliferators formed two separate clusters, confirming that they act through different mechanisms. Expression profiles of the hormone 17alpha-ethinylestradiol were not similar to any of the other compounds. In conclusion, gene expression profiles induced by compounds that act via similar mechanisms showed common effects on transcription upon treatment in vivo and in rat liver slices in vitro.
转录谱分析被用作一种体内方法，用于预测非遗传毒性致癌物的作用模式类别。为建立一个可靠的体外短期测试系统，将DNA微阵列技术与大鼠肝切片相结合。选择了七种已知作为肿瘤促进剂起作用的化合物，其中包括酶诱导剂苯巴比妥、α-六氯环己烷和醋酸环丙孕酮；过氧化物酶体增殖剂WY-14643、脱氢表雄酮和环丙贝特；以及激素17α-乙炔雌二醇。将大鼠肝切片暴露于不同浓度的化合物中24小时。使用包含约1500个基因的聚焦毒理学的TOXaminer DNA微阵列来生成每种测试化合物的基因表达谱。层次聚类分析表明：（i）体外在大鼠肝切片中生成的基因表达谱具有特异性，能够对具有相似作用模式的化合物进行分类；（ii）体外暴露的大鼠肝切片的表达谱与体内处理后诱导的表达谱相关（先前已报道）。酶诱导剂和过氧化物酶体增殖剂形成两个独立的聚类，证实它们通过不同机制起作用。激素17α-乙炔雌二醇的表达谱与其他任何化合物都不相似。总之，通过相似机制起作用的化合物诱导的基因表达谱在体内处理和体外大鼠肝切片处理时对转录显示出共同影响。
