title: Characterization of rat or human hepatocytes cultured in microphysiological systems (MPS) to identify hepatotoxicity.
abstract: The liver is the main site for drug and xenobiotics metabolism, including inactivation or bioactivation. In order to improve the predictability of drug safety and efficacy in clinical development, and to facilitate the evaluation of the potential human health effects from exposure to environmental contaminants, there is a critical need to accurately model human organ systems such as the liver in vitro. We are developing a microphysiological system (MPS) based on a new commercial microfluidic platform (Nortis, Inc.) that can utilize primary liver cells from multiple species (e.g., rat and human). Compared to conventional monolayer cell culture, which typically survives for 5-7days or less, primary rat or human hepatocytes in an MPS exhibited higher viability and improved hepatic functions, such as albumin production, expression of hepatocyte marker HNF4α and canaliculi structure, for up to 14days. Additionally, induction of Cytochrome P450 (CYP) 1A and 3A4 in cryopreserved human hepatocytes was observed in the MPS. The acute cytotoxicity of the potent hepatotoxic and hepatocarcinogen, aflatoxin B1, was evaluated in human hepatocytes cultured in an MPS, demonstrating the utility of this model for acute hepatotoxicity assessment. These results indicate that MPS-cultured hepatocytes provide a promising approach for evaluating chemical toxicity in vitro.
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Shih-Yu
authors.initials: SY
authors.lastname: Chang
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Jenna L
authors.initials: JL
authors.lastname: Voellinger
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Kirk P
authors.initials: KP
authors.lastname: Van Ness
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Chapron
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Shaffer
authors.affiliation: Nortis, Inc. Seattle, WA, 98102, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Neumann
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Collin C
authors.initials: CC
authors.lastname: White
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Terrance J
authors.initials: TJ
authors.lastname: Kavanagh
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Kelly
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA. Electronic address: deaton@uw.edu.
authors.forename: David L
authors.initials: DL
authors.lastname: Eaton
mesh_terms: D000328:Adult; D016604:Aflatoxin B1 / Q000633:toxicity; D000818:Animals; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury; D002648:Child; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005260:Female; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D051381:Rats; D018675:Toxicity Tests / Q000379:methods*; D055815:Young Adult
chemical_list: D051557:Hepatocyte Nuclear Factor 4; D016604:Aflatoxin B1; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A
keywords: Hepatotoxicity; Human hepatocytes; In vitro models; Microphysiological systems; Preclinical toxicology; ‘Liver-on-a-chip’