title: Transcriptomic hepatotoxicity signature of chlorpromazine after short- and long-term exposure in primary human sandwich cultures.
abstract: Drug-induced liver injury is the most frequent reason for market withdrawal of approved drugs, and is difficult to predict in animal models. Here, we analyzed transcriptomic data derived from short- and long-term cultured primary human hepatocytes (PHH) exposed to the well known human hepatotoxin chlorpromazine (CPZ). Samples were collected from five PHH cultures after short-term (1 and 3 days) and long-term (14 days) repeat daily treatment with 0.1 or 0.2 µM CPZ, corresponding to C(max). Two PHH cultures were additionally treated with 1 µM CPZ, and the three others with 0.02 µM CPZ. Differences in the total number of gene changes were seen between donors and throughout treatment. Specific transcriptomic hepatotoxicity signatures were created for CPZ and consisted of inflammation/hepatitis, cholestasis, and liver proliferation in all five donors, as well as fibrosis and steatosis, which were observed in four of five donors. Necrosis was present in three of five donors, and an indicative signature of cirrhosis was observed after long-term 14-day repeat treatment, also in three of five donors. The inter-donor variability in the inflammatory response to CPZ treatment was associated with variability in the strength of the response of the transcriptomic hepatotoxicity signatures, suggesting that features of inflammation could be related to the idiosyncratic hepatotoxic effects of CPZ in humans.
authors.affiliation: KaLy-Cell, Plobsheim, France (C.P., E.A., L.R.); Non-Clinical Safety, Merck Serono, Merck KGaA, Darmstadt, Germany (G.L.T., P.G.H., S.O.M.); Emergentec Biodevelopment GmbH, Vienna, Austria (K.M., A.L.); Department of Biostatistics, German Cancer Research Center, Heidelberg, Germany (S.S., A.K.-S.); Institut für Angewandte Biowissenschaften, Karlsruhe Institute of Technology, Karlsruhe, Germany (G.L.T., S.O.M.); and Laboratoire de Toxicologie Cellulaire, EA4267 Université de Franche-Comté, Besançon, France (L.R.).
authors.forename: Céline
authors.initials: C
authors.lastname: Parmentier
authors.forename: Germaine L
authors.initials: GL
authors.lastname: Truisi
authors.forename: Konrad
authors.initials: K
authors.lastname: Moenks
authors.forename: Sven
authors.initials: S
authors.lastname: Stanzel
authors.forename: Arno
authors.initials: A
authors.lastname: Lukas
authors.forename: Annette
authors.initials: A
authors.lastname: Kopp-Schneider
authors.forename: Eliane
authors.initials: E
authors.lastname: Alexandre
authors.forename: Philip G
authors.initials: PG
authors.lastname: Hewitt
authors.forename: Stefan O
authors.initials: SO
authors.lastname: Mueller
authors.forename: Lysiane
authors.initials: L
authors.lastname: Richert
mesh_terms: D000368:Aged; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics* / Q000378:metabolism*; D002746:Chlorpromazine / Q000008:administration & dosage* / Q000009:adverse effects*; D005260:Female; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D059467:Transcriptome / Q000235:genetics*
chemical_list: D002746:Chlorpromazine