Drug Non‑Clinical Evaluation and Research Center, Guangzhou General Pharmaceutical Research Institute, Haizhu, Guangzhou 510240, P.R. China.
Drug Safety Evaluation Center, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China.
Mol Med Rep. 2022 Oct;26(4). doi: 10.3892/mmr.2022.12830. Epub 2022 Aug 25.
Binaprofen (CHNO) is a drug not commercially available that causes liver injury; however, the underlying mechanism is unknown. The aim of the present study was to determine the mechanism underlying binaprofen‑induced liver injury at the genetic level. Zebrafish were treated with binaprofen. Serum biomarkers [alanine transaminase (ALT), aspartate transaminase (AST) and lactate dehydrogenase (LDH)], malondialdehyde (MDA) and glutathione (GSH) content analysis, liver cell morphology examination, DAPI staining, electron microscopy, microarray analysis and reverse transcription‑quantitative (RT‑q)PCR were performed 12, 24 and 48 h post‑treatment to analyze the mechanism underlying binaprofen‑induced liver injury. Following exposure to binaprofen, zebrafish serum levels of ALT, AST and LDH increased; MDA content of liver tissue increased and GSH content decreased. Liver cells exhibited mild to moderate vacuolization and mitochondria exhibited vacuolization and disrupted cristae. Liver cell apoptosis rate increased. There were 190 common differentially expressed genes at 12, 24 and 48 h. Gene Ontology analysis showed that the function of downregulated genes was primarily associated with 'DNA replication', 'DNA metabolic process', 'cell cycle', 'cell redox homeostasis', 'mitochondrion' and 'lipid transport'. The function of upregulated genes was primarily associated with 'peroxisome proliferator', 'oxidation activity', 'peroxisome' and 'apoptosis'. Pathway analysis showed that downregulated genes were those pertaining to 'cell cycle', 'DNA replication', 'ribosome', 'spliceosome', 'pyrimidine metabolism', 'purine metabolism', upregulated genes were those pertaining to 'PPAR signaling pathway', 'p53 signaling pathway'; RT‑qPCR assay supported the microarray results. The mechanism underlying binaprofen‑induced liver injury was associated with lipid peroxidation and apoptosis. Binaprofen downregulated genes associated with lipid transport and anti‑apoptosis genes, upregulated pro‑apoptosis genes and induces liver cell injury via the mitochondrial signaling pathway.
双布洛芬（CHNO）是一种尚未商业化的致肝损伤药物，但具体机制尚不清楚。本研究旨在从遗传水平上确定双布洛芬诱导肝损伤的机制。用双布洛芬处理斑马鱼。分别于处理后 12、24 和 48 h 时，检测血清生物标志物[丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）和乳酸脱氢酶（LDH）]、丙二醛（MDA）和谷胱甘肽（GSH）含量、肝组织细胞形态学检查、DAPI 染色、电镜检查、微阵列分析和反转录-定量（RT-q）PCR，以分析双布洛芬诱导肝损伤的机制。双布洛芬暴露后，斑马鱼血清 ALT、AST 和 LDH 水平升高；肝组织 MDA 含量增加，GSH 含量降低。肝细胞出现轻至中度空泡化，线粒体出现空泡化和嵴断裂。肝细胞凋亡率增加。在 12、24 和 48 h 时，有 190 个共同差异表达基因。GO 分析表明，下调基因的功能主要与“DNA 复制”、“DNA 代谢过程”、“细胞周期”、“细胞氧化还原稳态”、“线粒体”和“脂质转运”有关。上调基因的功能主要与“过氧化物酶体增殖物”、“氧化活性”、“过氧化物酶体”和“细胞凋亡”有关。通路分析表明，下调基因与“细胞周期”、“DNA 复制”、“核糖体”、“剪接体”、“嘧啶代谢”、“嘌呤代谢”有关，上调基因与“PPAR 信号通路”、“p53 信号通路”有关；RT-qPCR 检测支持微阵列结果。双布洛芬诱导肝损伤的机制与脂质过氧化和细胞凋亡有关。双布洛芬下调与脂质转运和抗凋亡基因有关，上调促凋亡基因，并通过线粒体信号通路诱导肝细胞损伤。
