Metazachlor: mode of action analysis for rat liver tumour formation and human relevance

Highlights•A comprehensive series of in vivo and in vitro experiments demonstrates that the herbicide metazachlor is a CAR activator in rat liver. •The work presents a robust mode of action analysis following the IPCS framework for the hepatocellular tumours observed in female Wistar rats. •The prop...

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Veröffentlicht in:	Toxicology (Amsterdam) 2019-10, Vol.426, p.152282-152282, Article 152282
Hauptverfasser:	Wiemann, Christiane, Goettel, Manuela, Vardy, Audrey, Elcombe, Barbara M, Elcombe, Clifford R, Chatham, Lynsey R, Wang, Hongbing, Li, Linhao, Buesen, Roland, Honarvar, Naveed, Treumann, Silke, Marxfeld, Heike, Groeters, Sibylle, Lake, Brian G
Format:	Artikel
Sprache:	eng
Schlagworte:	Acetamides - toxicity Animals Cells, Cultured Constitutive androstane receptor Coxsackie and Adenovirus Receptor-Like Membrane Protein - drug effects Coxsackie and Adenovirus Receptor-Like Membrane Protein - metabolism DNA Replication - drug effects Emergency Female Gene Knockout Techniques Hepatocytes - drug effects Hepatocytes - pathology Herbicides - toxicity Human relevance Humans Liver - pathology Liver Neoplasms, Experimental - chemically induced Liver Neoplasms, Experimental - pathology Liver tumour formation Male Metazachlor Mice Mice, Inbred C57BL Mode of action Organ Size - drug effects Rats Rats, Sprague-Dawley Rats, Wistar Replicative DNA synthesis Translocation, Genetic - drug effects
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Zusammenfassung:	Highlights•A comprehensive series of in vivo and in vitro experiments demonstrates that the herbicide metazachlor is a CAR activator in rat liver. •The work presents a robust mode of action analysis following the IPCS framework for the hepatocellular tumours observed in female Wistar rats. •The proposed mode of action for rat liver tumour formation is considered qualitatively not plausible for humans as metazachlor does not stimulate cell proliferation in human hepatocytes.
ISSN:	0300-483X 1879-3185
DOI:	10.1016/j.tox.2019.152282