Recently, we reported an in vitro toxicogenomics comparison approach to categorize chemical substances according to similarities in their proposed toxicological modes of action. Use of such an approach for regulatory purposes requires, among others, insight into the extent of biological concordance between in vitro and in vivo findings. To that end, we applied the comparison approach to transcriptomics data from the Open TG-GATEs database for 137 substances with diverging modes of action and evaluated the outcomes obtained for rat primary hepatocytes and for rat liver. The results showed that a relatively small number of matches observed in vitro were also observed in vivo, whereas quite a large number of matches between substances were found to be relevant solely in vivo or in vitro. The latter could not be explained by physicochemical properties, leading to insufficient bioavailability or poor water solubility. Nevertheless, pathway analyses indicated that for relevant matches the mechanisms perturbed in vitro are consistent with those perturbed in vivo. These findings support the utility of the comparison approach as tool in mechanism-based risk assessment.

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体外转录组学与体内作用方式评估的相关性

最近，我们报道了一种体外毒理学比较方法，可根据化学物质提出的毒理学作用模式的相似性对其进行分类。将这种方法用于监管目的，需要深入了解体外和体内发现之间的生物学一致性程度。为此，我们将比较方法应用于来自 Open TG-GATEs 数据库的 137 种具有不同作用模式的物质的转录组学数据，并评估了大鼠原代肝细胞和大鼠肝脏的结果。结果表明，体外观察到的匹配数量相对较少，体内也观察到了，而物质之间的大量匹配被发现仅在体内或体外相关。后者不能用理化性质解释，导致生物利用度不足或水溶性差。然而，通路分析表明，对于相关匹配，体外扰动的机制与体内扰动的机制一致。这些发现支持比较方法作为基于机制的风险评估工具的实用性。