• ABOUT
    • About INDIGO
    • Why INDIGO
    • Key Personnel
      • Board of Directors & Advisors
      • Management
    • Employment
    • INDIGO Press Releases
    • INDIGO in the News
  • ASSAYS
    • By Receptor
    • By Disease State
      • Overview
      • Anemia & Kidney Disease
      • Autoimmune Disease & Inflammation
      • Cancer
      • Cardiovascular Disease
      • Diabetes
      • Endocrinology
      • NAFLD/NASH
      • Obesity
    • Toxicology Solutions
      • In Vitro Toxicology Platform
      • Gene Expression
      • MDR1 / Human P-Glycoprotein
      • Discovery Toxicology
      • Environmental Monitoring
    • INDIGlo Luciferase Detection Reagent
    • Live Cell Multiplex
    • Ortholog Assays
    • Custom Assay Development
  • TECHNOLOGY
    • Nuclear Receptor Overview
    • Assay Kit Platform & Formats
    • Nuclear Receptor Profiling & Panels
    • Environmental Testing Solutions
    • Growth Factor Receptors
    • upcyte® Hepatocytes
    • FAQ
  • RESOURCES
    • Technical Manuals
    • Safety Data Sheets
    • Scientific Whitepapers from INDIGO
    • Scientific Posters
    • New Research Publications
    • Nuclear Receptor Resource
  • CONTACT US
    • Contact INDIGO
    • Request a Quote
    • Request Information
    • Distributors
    • Terms & Conditions
      • Product Policies
      • Limited Use Disclosures
  • BLOG
Search site...

± α β γ δ Δ ε ζ κ ω ö ® ™ µ

  • ABOUT
    • About INDIGO
    • Why INDIGO
    • Key Personnel
      • Board of Directors & Advisors
      • Management
    • Employment
    • INDIGO Press Releases
    • INDIGO in the News
  • ASSAYS
    • By Receptor
    • By Disease State
      • Overview
      • Anemia & Kidney Disease
      • Autoimmune Disease & Inflammation
      • Cancer
      • Cardiovascular Disease
      • Diabetes
      • Endocrinology
      • NAFLD/NASH
      • Obesity
    • Toxicology Solutions
      • In Vitro Toxicology Platform
      • Gene Expression
      • MDR1 / Human P-Glycoprotein
      • Discovery Toxicology
      • Environmental Monitoring
    • INDIGlo Luciferase Detection Reagent
    • Live Cell Multiplex
    • Ortholog Assays
    • Custom Assay Development
  • TECHNOLOGY
    • Nuclear Receptor Overview
    • Assay Kit Platform & Formats
    • Nuclear Receptor Profiling & Panels
    • Environmental Testing Solutions
    • Growth Factor Receptors
    • upcyte® Hepatocytes
    • FAQ
  • RESOURCES
    • Technical Manuals
    • Safety Data Sheets
    • Scientific Whitepapers from INDIGO
    • Scientific Posters
    • New Research Publications
    • Nuclear Receptor Resource
  • CONTACT US
    • Contact INDIGO
    • Request a Quote
    • Request Information
    • Distributors
    • Terms & Conditions
      • Product Policies
      • Limited Use Disclosures
  • BLOG

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

Print Friendly, PDF & Email

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.

View the full article HERE.

Date of publication: 13 December 2017; Oxford Academic: Toxicological Sciences, Volume 162 Issue 2 (available 1 April 2018)

Author information: Richard C Peffer (1); David E Cowie (2); Richard A Currie (2); Daniel J Minnema(1)

(1) Syngenta Crop Protection, LLC, Greensboro, North Carolina 27419-8300
(2) Syngenta Ltd., Jealott’s Hill International Research Center, Bracknell, Berkshire RG42 6EY, UK

Filed Under: New Publications Tagged With: AhR, CAR, constitutive androstane receptor, liver tumor, ortholog, PPARa, PPARα, PXR, sedaxane

Request a Quote Icon
Search site...
Click to Insert Symbols in Search

α β γ δ Δ ε ζ κ ® ™ µ

Want More Information?

Resource Quick Links

  • Technical Manuals & Product Listing
  • Safety Data Sheets
  • Sample Study Report
  • Study Work Order Form

3006 Research Drive, Suite A1, State College, PA, USA 16801

+1 (814) 234-1919

  • Home
  • Products
  • Request a Quote
  • FAQ

© 2022 INDIGO Biosciences, Inc. All Rights Reserved