Clinical characterization and mechanism exploration of Fructus Psoraleae-induced hepatotoxicity in zebrafish

doi:10.19803/j.1672-8629.20240317

Abstract

Abstract: Objective To investigate the effects of Fructus Psoraleae (FP) in accordance with clinical medicinal characteristics on the liver of zebrafish based on the proteome and its potential hepatotoxic mechanism. Methods Adult zebrafish were continuously treated with low, medium, and high concentrations of FP decoction (0.025, 0.050, 0.100 mg·mL^-1) for 21 days. Changes in zebrafish body weight, liver histopathology, and levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the serum detected by enzyme-linked immunosorbent assay (ELISA) were compared. Potential hepatotoxic mechanisms were studied based on identified liver proteome through cluster and pathway enrichment analysis, and molecular docking was used to explore potential toxic targets of the main hepatotoxic components of FP. Results Zebrafish treated with FP decoction showed a significant decrease in body weight compared to the control group, with a more pronounced weight loss as the concentration increased. The levels of ALT and AST were significantly elevated in the Angelica sinensis treated group, with a dose-dependent effect (P < 0.05). Hematoxylin-eosin (HE) staining results showed disordered arrangement of liver cells, increased gaps, and phenomena such as steatosis and immune cell infiltration in the liver tissues of the FP-treated group compared to the control group, with the severity of the lesions worsening with increasing concentration. Cluster and functional enrichment analysis of the proteome indicated that FP affected the expression of lipid and energy metabolism-related proteins, including acetyl-CoA acetyltransferase 1 (acat1), 3-hydroxyacyl-CoA dehydrogenase (ehhadh), succinate dehydrogenase (sdha) and succinate dehydrogenase (sdhb) in the zebrafish liver, and molecular docking revealed the potential of the main hepatotoxic components in FP to bind to these proteins. Conclusion Long-term Fructus Psoraleae administration causes hepatic lipid metabolism disorders, ultimately resulting in hepatotoxicity characterized by steatosis, with the potential toxicity mechanism involving abnormal expression of lipid and energy metabolism-related proteins induced by main hepatotoxic compounds in FP.

Key words: Fructus Psoraleae, hepatotoxic, steatosis, proteomics, lipid, energy, metabolism, molecular docking, zebrafish

CLC Number:

R965

AO Ting, WANG Ningning, ZHOU Lei, DENG Huifang, YANG Xingxin, ZHOU Wei, SHEN Pan, GAO Yue. Clinical characterization and mechanism exploration of Fructus Psoraleae-induced hepatotoxicity in zebrafish[J]. Chinese Journal of Pharmacovigilance, 2024, 21(6): 611-616.

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