title: Comparison of hepatocarcinogen-induced gene expression profiles in conventional primary rat hepatocytes with in vivo rat liver.
abstract: At present, substantial efforts are focused on the development of in vitro assays coupled with "omics" technologies for the identification of carcinogenic substances as an alternative to the classical 2-year rodent carcinogenicity bioassay. A prerequisite for the eventual regulatory acceptance of such assays, however, is the in vivo relevance of the observed in vitro findings. In the current study, hepatocarcinogen-induced gene expression profiles generated after the exposure of conventional cultures of primary rat hepatocytes to three non-genotoxic carcinogens (methapyrilene hydrochloride, piperonyl butoxide, and Wy-14643), three genotoxic carcinogens (aflatoxin B1, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, and 2-nitrofluorene), and two non-carcinogens (nifedipine and clonidine) are compared with previously obtained in vivo data after oral administration for up to 14 days of the same hepatocarcinogens to rats. In addition to the comparison of deregulated genes and functions per compound between in vivo and in vitro models, the major discriminating cellular pathways found in vivo in livers of exposed rats were examined for deregulation in vitro. Further, in vivo-derived gene signatures for the identification of genotoxic versus non-genotoxic carcinogens are used to classify in vitro-tested hepatocarcinogens and non-carcinogens. In the primary hepatocyte cultures, two out of the three tested genotoxic carcinogens mimicked the in vivo-relevant DNA damage response and were correctly assessed. Exposure to the non-genotoxic hepatocarcinogens, however, triggered a relatively weak response in the in vitro system, with no clear similarities to in vivo. This study contributes to the further optimization of toxicogenomics predictive tools when applied in in vitro settings.
authors.affiliation: Department of Toxicology, Center for Pharmaceutical Research, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium. tatyana.yordanova.doktorova@vub.ac.be
authors.forename: Tatyana Y
authors.initials: TY
authors.lastname: Doktorova
authors.forename: Heidrun
authors.initials: H
authors.lastname: Ellinger-Ziegelbauer
authors.forename: Mathieu
authors.initials: M
authors.lastname: Vinken
authors.forename: Tamara
authors.initials: T
authors.lastname: Vanhaecke
authors.forename: Joost
authors.initials: J
authors.lastname: van Delft
authors.forename: Jos
authors.initials: J
authors.lastname: Kleinjans
authors.forename: Hans-Juergen
authors.initials: HJ
authors.lastname: Ahr
authors.forename: Vera
authors.initials: V
authors.lastname: Rogiers
mesh_terms: D000818:Animals; D015197:Carcinogenicity Tests / Q000379:methods; D002273:Carcinogens / Q000494:pharmacology / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D004249:DNA Damage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D009153:Mutagens / Q000494:pharmacology / Q000633:toxicity*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D043922:Toxicogenetics / Q000379:methods
chemical_list: D002273:Carcinogens; D009153:Mutagens; D009363:Neoplasm Proteins; D012333:RNA, Messenger