沙利度胺对表达人细胞色素P450 3A的斑马鱼胸鳍致畸性的增强作用。

Augmentation of Pectoral Fin Teratogenicity by Thalidomide in Human Cytochrome P450 3A-Expressing Zebrafish.

作者信息

Dong Wenjing, Akasaka Ippo, Komiyama Akifumi, Nakamura Tatsuro, Mizoguchi Naohiro, Nawaji Tasuku, Ikushiro Shinichi, Kobayashi Makoto, Teraoka Hiroki

机构信息

School of Veterinary Medicine, Rakuno Gakuen University, 582, Bunkyodai-Midorimachi, Ebetsu, Hokkaido 069-8501, Japan.

Chemicals Evaluation and Research Institute, Japan (CERI), 3-2-7, Miyanojin, Kurume, 839-0801, Fukuoka, Japan.

出版信息

Pharmaceuticals (Basel). 2023 Feb 28;16(3):368. doi: 10.3390/ph16030368.

DOI:10.3390/ph16030368

PMID:36986467

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10055635/

Abstract

The pharmacological and toxicological effects of active metabolites of enzymes including cytochrome P450 (CYP) are important. While it has been believed for a long time that thalidomide causes characteristic limb malformation only in rabbits and primates including humans, the involvement of their CYP3A subtypes (CYP3As) has been suggested. Recently, however, it was reported that zebrafish were sensitive to thalidomide, showing defects of pectoral fins, homologous organs of forelimbs in mammals, as well as other deformities. In this study, we prepared human CYP3A7 (hCYP3A7)-expressing zebrafish (F0) using a transposon system. Thalidomide caused pectoral fin defects and other malformations including pericardial edema in hCYP3A7-expressing embryos/larvae but not in wild-type and hCYP1A1-expressing embryos/larvae. Thalidomide also reduced the expression of fibroblast growth factor 8 in pectoral fin buds in only hCYP3A7-expressing embryos/larvae. The results suggest the involvement of human-type CYP3A in thalidomide teratogenicity.

摘要

包括细胞色素P450（CYP）在内的酶的活性代谢产物的药理和毒理作用很重要。长期以来人们一直认为沙利度胺仅在兔子和包括人类在内的灵长类动物中导致特征性肢体畸形，有人提出这与它们的CYP3A亚型（CYP3As）有关。然而，最近有报道称斑马鱼对沙利度胺敏感，出现胸鳍缺陷，胸鳍是哺乳动物前肢的同源器官，以及其他畸形。在本研究中，我们使用转座子系统制备了表达人CYP3A7（hCYP3A7）的斑马鱼（F0）。沙利度胺在表达hCYP3A7的胚胎/幼体中导致胸鳍缺陷和其他畸形，包括心包水肿，但在野生型和表达hCYP1A1的胚胎/幼体中未出现。沙利度胺还仅在表达hCYP3A7的胚胎/幼体中降低了胸鳍芽中成纤维细胞生长因子8的表达。结果表明人源型CYP3A参与了沙利度胺的致畸作用。