Aquatic Ecology and Toxicology Group, Center for Organismal Studies, University of Heidelberg, Im Neuenheimer Feld 504, 69120, Heidelberg, Germany.
Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Nikolai-Fuchs-Strasse 1, 30625, Hannover, Germany.
Arch Toxicol. 2022 Nov;96(11):3033-3051. doi: 10.1007/s00204-022-03340-z. Epub 2022 Aug 3.
Valproic acid is a frequently used antiepileptic drug and known pediatric hepatotoxic agent. In search of pharmaceuticals with increased effectiveness and reduced toxicity, analogue chemicals came into focus. So far, toxicity and teratogenicity data of drugs and metabolites have usually been collected from mammalian model systems such as mice and rats. However, in an attempt to reduce mammalian testing while maintaining the reliability of toxicity testing of new industrial chemicals and drugs, alternative test methods are being developed. To this end, the potential of the zebrafish (Danio rerio) embryo to discriminate between valproic acid and 14 analogues was investigated by exposing zebrafish embryos for 120 h post fertilization in the extended version of the fish embryo acute toxicity test (FET; OECD TG 236), and analyzing liver histology to evaluate the correlation of liver effects and the molecular structure of each compound. Although histological evaluation of zebrafish liver did not identify steatosis as the prominent adverse effect typical in human and mice, the structure-activity relationship (SAR) derived was comparable not only to human HepG2 cells, but also to available in vivo mouse and rat data. Thus, there is evidence that zebrafish embryos might serve as a tool to bridge the gap between subcellular, cell-based systems and vertebrate models.
丙戊酸是一种常用的抗癫痫药物，也是一种已知的儿科肝毒性药物。为了寻找具有更高疗效和更低毒性的药物，类似物化学物质成为了研究重点。到目前为止，药物和代谢物的毒性和致畸性数据通常是从哺乳动物模型系统（如小鼠和大鼠）中收集的。然而，为了减少对哺乳动物的测试，同时保持对新工业化学品和药物毒性测试的可靠性，正在开发替代测试方法。为此，通过在扩展的鱼类胚胎急性毒性测试（FET；OECD TG 236）中对受精后 120 小时的斑马鱼胚胎进行暴露，研究了斑马鱼胚胎区分丙戊酸和 14 种类似物的潜力，并分析了肝脏组织学，以评估肝脏效应与每个化合物的分子结构之间的相关性。虽然斑马鱼肝脏的组织学评估没有发现脂肪肝是人类和小鼠中典型的突出不良反应，但得出的构效关系（SAR）不仅与人类 HepG2 细胞相似，而且与现有的体内小鼠和大鼠数据相似。因此，有证据表明斑马鱼胚胎可能成为一种工具，用于弥合亚细胞、基于细胞的系统和脊椎动物模型之间的差距。
