Critical evaluation of the human relevance of the mode of action for rodent liver tumor formation by activators of the constitutive androstane receptor (CAR)

Tomoya Yamada, Samuel M. Cohen, Brian G. Lake

Research output: Contribution to journalReview articlepeer-review

7 Scopus citations

Abstract

Many nongenotoxic chemicals have been shown to produce liver tumors in mice and/or rats by a mode of action (MOA) involving activation of the constitutive androstane receptor (CAR). Studies with phenobarbital (PB) and other compounds have identified the key events for this MOA: CAR activation; increased hepatocellular proliferation; altered foci formation; and ultimately the development of adenomas/carcinomas. In terms of human relevance, the pivotal species difference is that CAR activators are mitogenic agents in mouse and rat hepatocytes, but they do not stimulate increased hepatocellular proliferation in humans. This conclusion is supported by substantial in vitro studies with cultured rodent and human hepatocytes and also by in vivo studies with chimeric mice with human hepatocytes. Examination of the literature reveals many similarities in the hepatic effects and species differences between activators of rodent CAR and the peroxisome proliferator-activated receptor alpha (PPARα), with PPARα activators also not being mitogenic agents in human hepatocytes. Overall, a critical analysis of the available data demonstrates that the established MOA for rodent liver tumor formation by PB and other CAR activators is qualitatively not plausible for humans. This conclusion is supported by data from several human epidemiology studies.

Original languageEnglish (US)
Pages (from-to)373-394
Number of pages22
JournalCritical reviews in toxicology
Volume51
Issue number5
DOIs
StatePublished - 2021

Keywords

  • Cell proliferation
  • PXB mouse
  • chimeric mice
  • constitutive androstane receptor
  • cultured hepatocytes
  • human relevance
  • humanized models
  • mode of action
  • peroxisome proliferator-activated receptor alpha
  • phenobarbital
  • pregnane X receptor
  • rodent liver tumors
  • transgenic mice

ASJC Scopus subject areas

  • Toxicology

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