title: Toxicity monitoring with primary cultured hepatocytes underestimates the acetaminophen-induced inflammatory responses of the mouse liver.
abstract: In vitro gene expression profiling with isolated hepatocytes has been used to assess the hepatotoxicity of certain chemicals because of animal welfare issues.  However, whether an in vitro system can completely replace the in vivo system has yet to be elucidated in detail.  Using a focused microarray established in our laboratory, we examined gene expression profiles in the mouse liver and primary cultured hepatocytes after treatment with different doses of acetaminophen, a widely used analgesic that frequently causes liver injury.  The acute hepatotoxicity of acetaminophen was confirmed by showing the induction of an oxidative stress marker, heme oxygenase-1, elevated levels of serum transaminase, and histopathological findings.  In vivo microarray and network analysis showed that acetaminophen treatment provoked alterations in relation to the inflammatory response, and that tumor necrosis factor-α plays a central role in related pathway alterations.  By contrast, pathway analyses in in vitro isolated hepatocytes did not find such prominent changes in the inflammation-related networks compared with the in vivo situation.  Thus, although in vitro gene expression profiles are useful for evaluating the direct toxicity of chemicals, indirect toxicities including inflammatory responses mediated by cell-cell interactions or secondary toxicity due to pathophysiological changes in the whole body may be overlooked.  Our results indicate that the in vitro hepatotoxicity prediction system using isolated hepatocytes does not fully reflect the in vivo cellular response.  An in vitro system may be appropriate, therefore, for high throughput screening to detect the direct hepatotoxicity of a test compound.
authors.affiliation: Department of Public Health, University of Toyama, Toyama, Japan.
authors.forename: Shinjiro
authors.initials: S
authors.lastname: Tachibana
authors.forename: Akiko
authors.initials: A
authors.lastname: Shimomura
authors.forename: Hidekuni
authors.initials: H
authors.lastname: Inadera
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D008099:Liver / Q000187:drug effects* / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis
chemical_list: D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen