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Variable p53/Nrf2 crosstalk contributes to triptolide-induced hepatotoxic process.

Zhenyan Hou1, Miao Yan2, Huixiang Li3

  • 1State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Department of Pharmacy, Yantai Yuhuangding Hospital, Qingdao University, Yantai 264000, China.

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|March 29, 2023
PubMed
Summary
This summary is machine-generated.

Triptolide causes liver damage through a complex p53/Nrf2 interaction. Low doses activate protective pathways, while high doses trigger toxicity by inhibiting these same pathways.

Keywords:
CrosstalkLiver injuryNF-E2-related factor 2P53Self-protectionTriptolide

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Area of Science:

  • Hepatotoxicity Research
  • Molecular Toxicology
  • Cellular Stress Response

Background:

  • Triptolide is a compound known for its potential toxicity, particularly to the liver.
  • The precise molecular mechanisms underlying triptolide-induced hepatotoxicity remain incompletely understood.
  • The roles of key cellular regulators like p53 and Nrf2 in drug-induced liver injury are complex and context-dependent.

Purpose of the Study:

  • To elucidate the mechanism of triptolide-induced hepatotoxicity.
  • To investigate the novel and variable role of p53/Nrf2 crosstalk in this process.
  • To explore how different concentrations of triptolide affect the p53 and Nrf2 pathways.

Main Methods:

  • Treatment of cells or animal models with varying concentrations of triptolide.
  • Assessment of p53 and Nrf2 protein levels, nuclear translocation, and transcriptional activity.
  • Analysis of downstream target gene expression, including efflux transporters like MRPs and BSEP.
  • Investigation of physical interactions between p53 and Nrf2 using co-immunoprecipitation assays.

Main Results:

  • Low triptolide doses induced an adaptive stress response with enhanced Nrf2 and p53 activity, promoting cell survival.
  • High triptolide concentrations led to decreased Nrf2 levels and increased p53 nuclear translocation, resulting in hepatotoxicity.
  • Nrf2 and p53 exhibited dynamic physical interactions, with enhanced complex formation at low doses and dissociation at high doses.
  • p53/Nrf2 crosstalk showed concentration-dependent effects, shifting from pro-survival to pro-toxicity.

Conclusions:

  • Variable p53/Nrf2 crosstalk is a key determinant of triptolide-induced hepatotoxicity.
  • Low triptolide concentrations promote a protective crosstalk, while high concentrations disrupt this balance, leading to liver injury.
  • Modulating the p53/Nrf2 interaction presents a potential therapeutic strategy to mitigate triptolide-induced liver damage.