A new perspective of triptolide-associated hepatotoxicity: Liver hypersensitivity upon LPS stimulation

Toxicology. 2019 Feb 15:414:45-56. doi: 10.1016/j.tox.2019.01.005. Epub 2019 Jan 8.

Abstract

Objective: This study was designed to investigate whether the mice treated with triptolide (TP) could disrupt the liver immune homeostasis, resulting in the inability of the liver to eliminate the harmful response induced by lipopolysaccharide (LPS). In addition, we explored whether apoptosis and necroptosis played a critical role in the progression of the hepatotoxicity induced by TP-LPS co-treatment.

Methods: Female C57BL/6 mice were continuously administrated with two different doses of TP (250 μg/kg and 500 μg/kg) intragastrically for 7 days. Subsequently, a single dose of LPS (0.1 mg/kg) was injected intraperitoneally to testify whether the liver possesses the normal immune function to detoxicate the exogenous pathogen's stimulation. To prove the involvement of apoptosis and necroptosis in the liver damage induced by TP-LPS co-treatment, apoptosis inhibitor Z-VAD-FMK (FMK) and necroptosis inhibitor necrostatin (Nec-1) were applied before the stimulation of LPS to diminish the apoptosis and necroptosis respectively.

Results: TP or LPS alone did not induce significant liver damage. However, compared with TP or LPS treated mice, TP-LPS co-treatment mice showed obvious hepatotoxicity with a remarkable elevation of serum ALT and AST accompanied by abnormal bile acid metabolism, a depletion of liver glycogen storage, aberrant glucose metabolism, an up-regulation of inflammatory cell infiltration, and an increase of apoptosis and necroptosis. Intraperitoneal injection of FMK or Nec-1 could counteract the toxic reactions induced by TP-LPS co-treatment.

Conclusion: TP could disrupt the immune response, resulting in hypersensitivity of the liver upon LPS stimulation, ultimately leading to abnormal liver function and cell death. Additionally, apoptosis and necroptosis played a vital role in the development of liver damage induced by TP-LPS co-treatment.

Keywords: Apoptosis; Hepatotoxicity; LPS; Necroptosis; Triptolide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine Transaminase / blood
  • Amino Acid Chloromethyl Ketones / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Aspartate Aminotransferases / blood
  • Bile Acids and Salts / metabolism
  • Caspase Inhibitors / pharmacology
  • Chemical and Drug Induced Liver Injury / etiology*
  • Chemical and Drug Induced Liver Injury / immunology
  • Chemical and Drug Induced Liver Injury / metabolism
  • Chemical and Drug Induced Liver Injury / pathology
  • Diterpenes / toxicity*
  • Dose-Response Relationship, Drug
  • Epoxy Compounds / toxicity
  • Female
  • Glucose / metabolism
  • Glycogen / metabolism
  • Imidazoles / pharmacology
  • Immunologic Factors / toxicity*
  • Indoles / pharmacology
  • Lipopolysaccharides / toxicity*
  • Liver / drug effects*
  • Liver / immunology
  • Liver / metabolism
  • Liver / pathology
  • Mice, Inbred C57BL
  • Necrosis
  • Phenanthrenes / toxicity*
  • Signal Transduction / drug effects

Substances

  • Amino Acid Chloromethyl Ketones
  • Bile Acids and Salts
  • Caspase Inhibitors
  • Diterpenes
  • Epoxy Compounds
  • Imidazoles
  • Immunologic Factors
  • Indoles
  • Lipopolysaccharides
  • Phenanthrenes
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
  • necrostatin-1
  • triptolide
  • Glycogen
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • Glucose