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Receptor-mediated hepatocarcinogenesis: role of hepatocyte proliferation and apoptosis

Jason D Oliver1, Ruth A Roberts

  • 1Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire SK10 4TJ, UK. jason.oliver@syngenta.com

Pharmacology & Toxicology
|August 24, 2002
PubMed

Insights

Non-genotoxic carcinogens disrupt rodent liver homeostasis by affecting cell death and proliferation. Receptor activity is essential for this toxicity, highlighting key gene expression changes in hepatocyte responses.

Area of Science:

  • Toxicology
  • Hepatology
  • Molecular Biology

Background:

  • Rodent liver is a target for non-genotoxic carcinogens like dioxins and PCBs.
  • These chemicals disrupt liver homeostasis by altering hepatocyte cell death and proliferation, leading to hyperplasia and tumors.

Purpose of the Study:

  • To elucidate the mechanisms of action for non-genotoxic carcinogens in the rodent liver.
  • To investigate the role of specific xenobiotic receptors in toxicant-induced liver toxicity.

Main Methods:

  • Investigated the binding of dioxins, PCBs, phenobarbital, and peroxisome proliferators to specific receptors.
  • Utilized transgenic mouse models with disrupted genes for aryl hydrocarbon receptor, constitutive androstane receptor, and activated receptor alpha.
  • Analyzed ligand-dependent transcription activities and changes in gene expression.

Main Results:

  • Identified key receptors: aryl hydrocarbon receptor (dioxins, PCBs), constitutive androstane receptor (phenobarbital), and activated receptor alpha (peroxisome proliferators).
  • Demonstrated that receptor activity is essential for the toxicity of these carcinogens.
  • Showed that altered gene expression controlling proliferation and apoptosis is critical in the xenobiotic-induced hepatocyte phenotype.

Conclusions:

  • Specific xenobiotic receptors mediate the toxic effects of non-genotoxic carcinogens on the rodent liver.
  • Target gene expression changes are crucial in the development of xenobiotic-induced hepatocyte hyperplasia and tumor formation.

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