title: Investigation of the hepatotoxicity profile of chemical entities using Liverbeads and WIF-B9 in vitro models.
abstract: The cytotoxicity profile of various chemical entities was evaluated using two in vitro hepatocyte models. Liverbeads is a cryopreserved model consisting of primary hepatocytes entrapped in alginate beads. WIF-B9 is a hybrid cell line obtained by fusion of rat hepatoma (Fao) and human fibroblasts (WI38). Various reference hepatotoxicants were tested and ranked according to their equivalent concentration 50 (EC50) for various biochemical endpoints (lactate dehydrogenase (LDH) release, 3-(4,5 dimethylthiazol 2yl)-2,5-diphenyl-2H tetrazolium bromure (MTT) activity, adenosine triphosphate (ATP) and glutathione (GSH) levels). The ranking obtained was comparable in both models and consistent with previously published results on hepatocyte monolayers. Ketoconazole, erythromycin estolate, retinoic acid, telithromycin and alpha-naphthyl-isothiocyanate were among the most toxic chemicals in both models, with an EC50 < 200 microM. Troleandomycin, spiramycin, erythromycin, diclofenac, taurodeoxycholate, warfarin, galactosamine, valproic acid and isoniazid were found to be less toxic. Few marked differences, potentially linked to metabolism pathways, were observed between EC50s in the two models for compounds such as cyclosporine A (10 and > 831 microM) and warfarin (5904 and 1489 microM) in WIF-B9 and Liverbeads, respectively. The results obtained indicate that Liverbeads and WIF-B9 cells are reliable in vitro models to evaluate the hepatotoxic potential of a wide range of chemicals, irrespective of structure and pharmaceutical class.
authors.affiliation: Pfizer Global R&D, Safety Sciences Europe, Z.I. Pocé sur Cisse, 37401 Amboise, France. christine.biagini@pfizer.com
authors.forename: Christine P
authors.initials: CP
authors.lastname: Biagini
authors.forename: Elodie
authors.initials: E
authors.lastname: Boissel
authors.forename: Françoise
authors.initials: F
authors.lastname: Borde
authors.forename: Virginie E
authors.initials: VE
authors.lastname: Bender
authors.forename: Michale
authors.initials: M
authors.lastname: Bouskila
authors.forename: Fabien
authors.initials: F
authors.lastname: Blazy
authors.forename: Laetitia
authors.initials: L
authors.lastname: Nicaise
authors.forename: Aurélien
authors.initials: A
authors.lastname: Mignot
authors.forename: Doris
authors.initials: D
authors.lastname: Cassio
authors.forename: Stephan
authors.initials: S
authors.lastname: Chevalier
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006822:Hybrid Cells / Q000187:drug effects*; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D013778:Tetrazolium Salts / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D013778:Tetrazolium Salts; D013844:Thiazoles; D000255:Adenosine Triphosphate; D003577:Cytochrome P-450 Enzyme System; C022616:thiazolyl blue; D005978:Glutathione