Expert workshop guidance on nuclear receptor-mediated liver toxicity – publication selected for prestigious SOT Risk Assessment award

CXR is pleased to announce that the recent publication entitled “Mode of action and human relevance analysis for nuclear receptor-mediated liver toxicity: A case study with phenobarbital as a model constitutive androstane receptor (CAR) activator” has been selected for a prestigious risk assessment award at the Society Of Toxicology (SOT) 2014 annual meeting.

CXR co-founder and Research Director Dr Cliff Elcombe co-chaired the workshop on which the paper was based with Douglas Wolf of the US Environmental Protection Agency, the paper was co-authored by Brian Lake of the Centre for Toxicology, University of Surrey, UK.

The paper has been selected by a committee of the Risk Assessment Specialty Section of the SOT as one of the Best Papers Published in 2013 Demonstrating Application of Risk Assessment.  The paper, published in the journal Critical Reviews in Toxicology, is based on the conclusions of a workshop organised by Toxicology Excellence for Risk Assessment (TERA) and attended by experts from regulators, industry and academia.  The public workshop was held at the National Institute of Environmental Health Sciences (NIEHS) in Research Triangle Park, North Carolina on September 27-29, 2010. Case studies were used to address activation of the aryl hydrocarbon receptor (AHR); the constitutive androstane receptor/Pregnane X receptor (CAR/PXR), and the peroxisome proliferator-activated receptor-alpha (PPARα). Other panel participnts were drawn from Syngenta Crop Protection, Dow Agrosciences, Bayer CropScience, the European Chemicals Agency, Auburn University, CellzDirect/Life Technologies, Dow Chemical Company, Michigan State University, the U.S. Food and Drug Administration-CDER, Penn State University, the University of Pittsburgh, and the University of Surrey.

Many non-genotoxic pharmaceuticals, agrochemicals and chemicals increase the incidence of rodent liver tumours during long term carcinogenicity studies. Faced with a compound that has caused (or is expected to cause) rodent tumours, it is necessary to demonstrate the relevance or irrelevance to humans to the satisfaction of regulatory bodies. The activation of nuclear receptors, including the Constitutive Androstane Receptor (CAR), is a common Mode of Action (MOA) for chemicals that exhibit non-genotoxic hepatocarcinogenicity in rodents.  The workshop recommended that if data indicates a compound induces liver tumours (or could be reasonably expected to induce liver tumours, based on a likelihood that it is a nuclear receptor ligand), the following framework can be suggested to specifically confirm a nuclear receptor mediated mode of action:

  • Confirm non-genotoxicty.
  • Exclude cytotoxicity.
  • Exclude non-CAR receptor MOAs.
  • Perform appropriate rodent studies to examine endpoints including:
    • Early, observable key and associative events (e.g. cell proliferation, CYP2B induction, apoptosis suppression, hypertrophy, liver weight).
    • Evaluate dose–response
  • CAR null animal study to show lack of effects.
  • CAR activation/nuclear translocation assays – if suitable models are available and valid.
  • Confirmation of lack of human relevance via CAR MOA, e.g. use of primary human hepatocytes and when appropriate humanized models.
  • If more than one nuclear receptor is activated, use selective receptor knockout animals.

About CXR

Founded in 2001, CXR Biosciences® uses its collaborative approach and toxicological expertise to help customers of all sizes solve issues relating to the safety of compounds or selection of research candidates. CXR offers tailored preclinical services in the areas of investigative & mechanistic toxicology, exploratory & discovery toxicology and PK & metabolism.  CXR uses a multidisciplinary approach, consistent with that advocated by the workshop, to evaluate the risk to humans of chemicals and pharmaceuticals that elicit a carcinogenic response in rodents, developed over many years of assisting global pharmaceutical, chemical and agrochemical companies.  These studies are frequently included in regulatory submissions.  CXR Biosciences® is located in Dundee, Scotland, United Kingdom.

References

Elcombe et al. (2013). Crit Rev Toxicol. January 2014, Vol. 44, No. 1 , Pages 64-82. “Mode of action and human relevance analysis for nuclear receptor-mediated liver toxicity: A case study with phenobarbital as a model constitutive androstane receptor (CAR) activator.”