Sedaxane-Use of Nuclear Receptor Transactivation Assays, Toxicogenomics, and Toxicokinetics as Part of a Mode of Action Framework for Rodent Liver Tumors

Toxicol Sci. 2018 Apr 1;162(2):582-598. doi: 10.1093/toxsci/kfx281.

Abstract

Experimental data demonstrate a mode of action (MOA) for liver tumors in male rats and mice treated with sedaxane that starts with activation of CAR, followed by altered expression of CAR-responsive genes, increased cell proliferation, and eventually clonal expansion of preneoplastic cells, leading to the development of altered foci and tumors. This MOA is nonrelevant to human risk assessments. Methods and results in the MOA work for sedaxane illustrate promising directions that future MOA studies may be able to employ, in the spirit of "Tox21" and reduction of in vivo animal use: (1) currently available in vitro CAR and PXR reporter assays demonstrated that sedaxane is a direct CAR activator in mice and rats, and a weak PXR activator in rats; (2) mouse liver microarray results compared with a published CAR biomarker signature (based on 83 genes) showed a clear, statistical match, and a lack of correlation to similar biomarker signatures for AhR, PPARα, and STAT5B; (3) Ki67 immunohistochemistry and zonal image analysis showed significant increases in this marker of cell proliferation in mouse liver, without the need to dose a DNA labeling agent; and (4) toxicokinetic analysis of Cmax levels of sedaxane in blood showed a marked species difference between mice and rats that helps to explain differences in sensitivity to sedaxane. Incorporating these tools into the study plan for a new agrochemical or drug during development offers a promising alternative to the traditional need to conduct later, specialized MOA studies after the results of chronic bioassays are known.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anilides / blood
  • Anilides / toxicity*
  • Animals
  • Dose-Response Relationship, Drug
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Liver Neoplasms, Experimental / chemically induced*
  • Liver Neoplasms, Experimental / genetics
  • Male
  • Mice, Inbred Strains
  • Pregnane X Receptor / genetics*
  • Primary Cell Culture
  • Pyrazoles / blood
  • Pyrazoles / toxicity*
  • Rats, Wistar
  • Receptors, Cytoplasmic and Nuclear / genetics*
  • Species Specificity
  • Toxicogenetics
  • Toxicokinetics
  • Transcriptional Activation / drug effects*

Substances

  • Anilides
  • N-(2-(1,1'-bicyclopropyl)-2-ylphenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide
  • Pregnane X Receptor
  • Pyrazoles
  • Receptors, Cytoplasmic and Nuclear
  • constitutive androstane receptor