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<p><i>Dysosma versipellis</i> (DV), despite its broad-spectrum antitumor potential, faces clinical limitations due to cholestatic hepatotoxicity, prompting investigation into its mechanisms and environmental health implications. Using a toxicological evidence chain (TEC) approach in Sprague–Dawley rats administered 1.2&#xa0;g/kg DV ethanol extract for 3&#xa0;days, integrated analyses revealed characteristic cholestatic injury, including significantly reduced liver weight (<i>P</i> &lt; 0.01), elevated serum biomarkers (ALT, AST, TBA; <i>P</i> &lt; 0.01), and bile duct hyperplasia. Toxicokinetic profiling identified five hepatotoxic podophyllotoxin derivatives (podophyllotoxin, 4'-demethylpodophyllotoxin, α-peltatin, β-peltatin, deoxypodophyllotoxin), with podophyllotoxin showing the highest systemic exposure (AUC₀₋ₜ). Bile acid metabolomics demonstrated profound dysregulation, notably a 6.9-fold increase in taurochenodeoxycholic acid (TCDCA) and a 78% decrease in glycocholic acid (GCA). Transcriptomics and mechanistic validation (RT-qPCR/Western blot) revealed suppression of the hepatic Farnesoid X Receptor (FXR)-Small Heterodimer Partner (SHP) axis, driving cholesterol 7α-hydroxylase (CYP7A1) upregulation and concurrent downregulation of canalicular transporters bile salt export pump (BSEP) and multidrug resistance-associated protein 2 (MRP2). These findings indicate that DV-induced cholestasis is mediated by podophyllotoxin derivatives through dual mechanisms: CYP7A1-driven bile acid overproduction via FXR-SHP inhibition and BSEP/MRP2-mediated excretion impairment, providing a molecular basis for detoxification strategies and environmental risk assessment of phytotoxin exposure.</p> Graphical abstract <p></p>

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Dysosma versipellis is associated with cholestatic hepatotoxicity potentially involving FXR-SHP-CYP7A1/BSEP-MRP2 axis disruption: A multi-omics-driven mechanistic investigation based on the toxicological evidence chain (TEC) concept

  • 期刊论文

  • 发表日期：

    2026年3月4日

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  • Yuanyang Shao,
  • Ding Li,
  • Lei Wang,
  • Xiaobin Huang,
  • Xun Chen,
  • Jiao Kong,
  • Suoyan Tian,
  • Yan Lei,
  • Chuanxin Liu

摘要

Dysosma versipellis (DV), despite its broad-spectrum antitumor potential, faces clinical limitations due to cholestatic hepatotoxicity, prompting investigation into its mechanisms and environmental health implications. Using a toxicological evidence chain (TEC) approach in Sprague–Dawley rats administered 1.2 g/kg DV ethanol extract for 3 days, integrated analyses revealed characteristic cholestatic injury, including significantly reduced liver weight (P < 0.01), elevated serum biomarkers (ALT, AST, TBA; P < 0.01), and bile duct hyperplasia. Toxicokinetic profiling identified five hepatotoxic podophyllotoxin derivatives (podophyllotoxin, 4'-demethylpodophyllotoxin, α-peltatin, β-peltatin, deoxypodophyllotoxin), with podophyllotoxin showing the highest systemic exposure (AUC₀₋ₜ). Bile acid metabolomics demonstrated profound dysregulation, notably a 6.9-fold increase in taurochenodeoxycholic acid (TCDCA) and a 78% decrease in glycocholic acid (GCA). Transcriptomics and mechanistic validation (RT-qPCR/Western blot) revealed suppression of the hepatic Farnesoid X Receptor (FXR)-Small Heterodimer Partner (SHP) axis, driving cholesterol 7α-hydroxylase (CYP7A1) upregulation and concurrent downregulation of canalicular transporters bile salt export pump (BSEP) and multidrug resistance-associated protein 2 (MRP2). These findings indicate that DV-induced cholestasis is mediated by podophyllotoxin derivatives through dual mechanisms: CYP7A1-driven bile acid overproduction via FXR-SHP inhibition and BSEP/MRP2-mediated excretion impairment, providing a molecular basis for detoxification strategies and environmental risk assessment of phytotoxin exposure.

Graphical abstract