Comparative Perinatal Development, Department of Veterinary Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
Laboratory of Molecular, Cellular and Network Excitability, Department of Biomedical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
Int J Mol Sci. 2021 Nov 24;22(23):12696. doi: 10.3390/ijms222312696.
The zebrafish () embryo is gaining interest as a bridging tool between in-vitro and in-vivo developmental toxicity studies. However, cytochrome P450 (CYP)-mediated drug metabolism in this model is still under debate. Therefore, we investigated the potential of zebrafish embryos and larvae to bioactivate two known anti-epileptics, carbamazepine (CBZ) and phenytoin (PHE), to carbamazepine-10,11-epoxide (E-CBZ) and 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH), respectively. First, zebrafish were exposed to CBZ, PHE, E-CBZ and HPPH from 5¼- to 120-h post fertilization (hpf) and morphologically evaluated. Second, the formations of E-CBZ and HPPH were assessed in culture medium and in whole-embryo extracts at different time points by targeted LC-MS. Finally, E-CBZ and HPPH formation was also assessed in adult zebrafish liver microsomes and compared with those of human, rat, and rabbit. The present study showed teratogenic effects for CBZ and PHE, but not for E-CBZ and HPPH. No HPPH was detected during organogenesis and E-CBZ was only formed at the end of organogenesis. E-CBZ and HPPH formation was also very low-to-negligible in adult zebrafish compared with the mammalian species. As such, other metabolic pathways than those of mammals are involved in the bioactivation of CBZ and PHE, or, these anti-epileptics are teratogens and do not require bioactivation in the zebrafish.
斑马鱼（）胚胎作为一种在体外和体内发育毒性研究之间的桥梁工具，越来越受到关注。然而，该模型中的细胞色素 P450（CYP）介导的药物代谢仍存在争议。因此，我们研究了斑马鱼胚胎和幼鱼将两种已知的抗癫痫药物卡马西平（CBZ）和苯妥英（PHE）生物转化为卡马西平-10,11-环氧化物（E-CBZ）和 5-（4-羟基苯基）-5-苯基乙内酰脲（HPPH）的潜力。首先，将斑马鱼从受精后 5¼ 小时至 120 小时（hpf）暴露于 CBZ、PHE、E-CBZ 和 HPPH 中，并进行形态评估。其次，通过靶向 LC-MS 在不同时间点评估培养介质中和整个胚胎提取物中 E-CBZ 和 HPPH 的形成。最后，还在成年斑马鱼肝微粒体中评估了 E-CBZ 和 HPPH 的形成，并与人类、大鼠和兔的微粒体进行了比较。本研究显示 CBZ 和 PHE 具有致畸作用，但 E-CBZ 和 HPPH 没有。在器官发生期间未检测到 HPPH，并且仅在器官发生结束时形成 E-CBZ。与哺乳动物物种相比，成年斑马鱼中 E-CBZ 和 HPPH 的形成也非常低或可忽略不计。因此，CBZ 和 PHE 的生物转化涉及除哺乳动物以外的其他代谢途径，或者这些抗癫痫药是致畸剂，不需要在斑马鱼中进行生物转化。
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