@article{1746959dd3094fd88a90609a001bb7a5,
title = "Critical evaluation of the human relevance of the mode of action for rodent liver tumor formation by activators of the constitutive androstane receptor (CAR)",
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.",
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",
author = "Tomoya Yamada and Cohen, {Samuel M.} and Lake, {Brian G.}",
note = "Funding Information: The authors gratefully acknowledge Dr. Chris Corton (US.EPA, Research Triangle Park, NC, USA) for discussions on the interpretation of the results of gene array studies for compounds which are CAR activators in rodent liver; Dr. Chise Tateno (PhoenixBio Co., Ltd., Higashi-Hiroshima, Japan) for review and valuable comment on the draft manuscript in particular of characterization and application of chimeric mouse models; members of Environmental Health Science Laboratory, Sumitomo Chemical Company, Ltd. for their encouragement to write this manuscript; and to the external reviewers selected by the Editor and anonymous to the authors whose comments were very valuable in revising and refining the manuscript. All authors gave final approval and agreed to be accountable for all aspects of work in ensuring that questions relating to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Funding Information: Dr. Tomoya Yamada is employed by Sumitomo Chemical Company, Ltd. Prof. Samuel M. Cohen and Prof. Brian G. Lake consult for Sumitomo Chemical Company, Ltd. regarding research on CAR activators as well as other matters. The manuscript was written as part of the authors{\textquoteright} normal employment, but the authors have sole responsibility for the writing and content of this paper. The views presented in this manuscript are those of the authors based on many years of research in the respective areas of investigation reported in this paper. This work was supported by the Sumitomo Chemical Company, Ltd. ( https://www.sumitomo-chem.co.jp/english/company/ ). This company is interested in the human relevance of the CAR-mediated MOA for rodent liver tumor formation, because some company products (e.g. pesticides) have CAR activation activity in rodent liver. Some of the research on CAR activators produced by Sumitomo Chemical Company, Ltd. has been utilized by the company in regulatory submissions to provide MOA information for interpreting the relevance to humans of the liver tumors in rodents. An additional review of the paper for internal approval purposes was conducted by Dr. Yoshitaka Tomigahara, a previous research director of Environmental Health Science Laboratory, Sumitomo Chemical Company, Ltd. No external funding was obtained for manuscript preparation. None of the authors has appeared in any legal or regulatory proceedings related to the contents of this paper. No potential conflict of interest was reported by the authors. Publisher Copyright: {\textcopyright} 2021 Sumitomo Chemical Company, Ltd. Published by Informa UK Limited, trading as Taylor & Francis Group.",
year = "2021",
doi = "10.1080/10408444.2021.1939654",
language = "English (US)",
volume = "51",
pages = "373--394",
journal = "Critical reviews in toxicology",
issn = "1040-8444",
publisher = "Informa Healthcare",
number = "5",
}