Shin Yoo-Sub, Hwang Da-Bin, Won Dong-Hoon, Kim Shin-Young, Kim Changuk, Park Jun Won, Jeon Young, Yun Jun-Won
Department of Research and Development, SML Genetree, Seoul, 05855 Republic of Korea.
Department of Biotechnology, The Catholic University of Korea, Bucheon, 14662 Republic of Korea.
Toxicol Res. 2023 Apr 14;39(3):443-453. doi: 10.1007/s43188-023-00180-6. eCollection 2023 Jul.
Drug-induced liver injury (DILI) is a major cause of acute liver failure and drug withdrawal. Cytochrome P450 (CYP) 2E1 is involved in the metabolism of several drugs, and can induce liver injury through the production of toxic metabolites and the generation of reactive oxygen species. This study aimed to elucidate the role of Wnt/β-catenin signaling in CYP2E1 regulation for drug-induced hepatotoxicity. To achieve this, mice were administered cisplatin or acetaminophen (APAP) 1 h after treatment with the CYP2E1 inhibitor dimethyl sulfoxide (DMSO), and histopathological and serum biochemical analyses were performed. APAP treatment induced hepatotoxicity, as evidenced by an increase in liver weight and serum ALT levels. Moreover, histological analysis indicated severe injury, including apoptosis, in the liver tissue of APAP-treated mice, which was confirmed by TUNEL assay. Additionally, APAP treatment suppressed the antioxidant capacity of the mice and increased the expression of the DNA damage markers γ-H2AX and p53. However, these effects of APAP on hepatotoxicity were significantly attenuated by DMSO treatment. Furthermore, the activation of Wnt/β-catenin signaling using the Wnt agonist CHIR99021 (CHIR) increased CYP2E1 expression in rat liver epithelial cells (WB-F344), whereas treatment with the Wnt/β-catenin antagonist IWP-2 inhibited nuclear β-catenin and CYP2E1 expression. Interestingly, APAP-induced cytotoxicity in WB-F344 cells was exacerbated by CHIR treatment and suppressed by IWP-2 treatment. Overall, these results showed that the Wnt/β-catenin signaling is involved in DILI through the upregulation of CYP2E1 expression by directly binding the transcription factor β-cat/TCF to the promoter, thus exacerbating DILI.
The online version contains supplementary material available at 10.1007/s43188-023-00180-6.
药物性肝损伤（DILI）是急性肝衰竭和药物撤药的主要原因。细胞色素P450（CYP）2E1参与多种药物的代谢，并可通过产生有毒代谢物和活性氧的生成诱导肝损伤。本研究旨在阐明Wnt/β-连环蛋白信号在CYP2E1调控药物性肝毒性中的作用。为此，在用CYP2E1抑制剂二甲基亚砜（DMSO）处理1小时后，给小鼠施用顺铂或对乙酰氨基酚（APAP），并进行组织病理学和血清生化分析。APAP处理诱导肝毒性，肝脏重量和血清ALT水平升高证明了这一点。此外，组织学分析表明，APAP处理的小鼠肝脏组织存在严重损伤，包括凋亡，TUNEL检测证实了这一点。此外，APAP处理抑制了小鼠的抗氧化能力，并增加了DNA损伤标志物γ-H2AX和p53的表达。然而，DMSO处理显著减轻了APAP对肝毒性的这些影响。此外，使用Wnt激动剂CHIR99021（CHIR）激活Wnt/β-连环蛋白信号增加了大鼠肝上皮细胞（WB-F344）中CYP2E1的表达，而用Wnt/β-连环蛋白拮抗剂IWP-2处理则抑制了核β-连环蛋白和CYP2E1的表达。有趣的是，CHIR处理加剧了APAP诱导的WB-F344细胞的细胞毒性，而IWP-2处理则抑制了这种毒性。总体而言，这些结果表明，Wnt/β-连环蛋白信号通过转录因子β-cat/TCF直接结合启动子上调CYP2E1表达而参与DILI，从而加剧DILI。
在线版本包含可在10.1007/s43188-023-00180-6获取的补充材料。
