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

Autor: Yamada T; Environmental Health Science Laboratory, Sumitomo Chemical Company, Ltd., Osaka, Japan., Cohen SM; Department of Pathology and Microbiology, Havlik-Wall Professor of Oncology, University of Nebraska Medical Center, Nebraska Medical Center, Omaha, NE, USA., Lake BG; Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK.
Jazyk: angličtina
Zdroj: Critical reviews in toxicology [Crit Rev Toxicol] 2021 May; Vol. 51 (5), pp. 373-394. Date of Electronic Publication: 2021 Jul 15.
DOI: 10.1080/10408444.2021.1939654
Abstrakt: 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.
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje