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Published on: November 15, 2013

Extrahepatic cancer suppresses nuclear receptor-regulated drug metabolism

Marina Kacevska1, Michael R Downes, Rohini Sharma

  • 1Storr Liver Unit, Westmead Millennium Institute, University of Sydney, Westmead, New South Wales, Australia.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|April 19, 2011
PubMed
Abstract

Insights

Extrahepatic tumors disrupt liver drug metabolism by altering nuclear receptors, impacting chemotherapy effectiveness and potentially causing toxicity. Understanding these mechanisms can guide treatment strategies.

Area of Science:

  • Pharmacology and Toxicology
  • Cancer Biology
  • Hepatology

Background:

  • Extrahepatic tumors can significantly alter hepatic drug clearance.
  • Altered drug metabolism contributes to variable drug response and chemotherapy resistance.
  • Understanding these systemic effects is crucial for optimizing cancer therapy.

Purpose of the Study:

  • To elucidate the mechanisms by which extrahepatic tumors modify hepatic drug clearance.
  • To investigate the role of nuclear receptors and transcription factors in these alterations.
  • To identify potential targets for intervention to normalize drug metabolism in cancer patients.

Main Methods:

  • Utilized wild-type and transgenic CYP3A4 reporter mice bearing extrahepatic tumors (murine Engelbreth-Holm-Swarm sarcoma).
  • Assessed changes in nuclear receptor and hepatic transcription factor expression and function, focusing on CYP3A gene regulation.
  • Quantified nuclear receptor expression and nuclear accumulation in hepatocytes.

Main Results:

  • Extrahepatic tumors dramatically repressed hepatic CYP3A induction, linked to reduced C/EBPβ isoforms and impaired pregnane X receptor (PXR) and constitutive androstane receptor (CAR) function.
  • Tumors significantly reduced nuclear accumulation of retinoid X receptor alpha (RXRα) in hepatocytes, affecting RXRα-dependent nuclear receptor function.
  • Expression of 14 out of 38 liver nuclear receptors, including CAR, Pparα, and Lxrβ, was reduced in tumor-bearing mice, indicating widespread metabolic dysregulation.

Conclusions:

  • Extrahepatic malignancy profoundly impacts hepatic drug metabolism through nuclear receptor relocalization, decreased expression, and impaired function.
  • These findings provide insights into chemotherapy resistance and toxicity.
  • Intervention strategies can be designed to normalize drug clearance and metabolic pathways in cancer patients.

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