Determination of Acute Lethal and Chronic Lethal Thresholds of Valproic Acid using 3D Spheroids Constructed from the Immortal Human Hepatocyte Cell Line Hepg2/C3A
Year: 2013
Type: book-chapter
Abstract: Valproic acid (VPA) is a broad-spectrum antiepileptic drug that is now used commonly for several other neurological and psychiatric indications. While VPA is usually well tolerated, on rare occasions, it has been associated with severe, and sometimes, fatal liver injuries. These complications may also arise due to acute VPA overdose. As a branched chain carboxylic acid, VPA is readily metabolized in the liver via glucuronic acid conjugation, mitochondrial β- and cytosolic ω-oxidation to produce multiple metabolites, and it is probably some of these metabolites that are involved in its toxicity. While the actual mechanism of VPA hepatotoxicity is still not understood, two pathways have been in focus: the first involves the formation of reactive metabolites of VPA (and their subsequent covalent binding to cellular proteins) and the second is the development of oxidative stress in the cell. We describe here a culture system based on 3D spheroid culture of immortal hepatocytes which can determine the toxicity of valproic acid (or structurally or functionally related molecules) in vitro. The spheroids were used to follow changes in ATP production, glucose uptake and adenylate kinase following treatment and can be treated repeatedly with VPA to determine both acutely-lethal and chronically-lethal doses. This system is homeostatic and has been shown to be metabolically stable over at least 24 days and can therefore be used to follow recovery after treatment. © 2013 Nova Science Publishers, Inc. All rights reserved.
Authors: Stephen J. Fey, Krzysztof Wrzesinski
Language: English
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: green
Funder: Syddansk Universitet
OpenAlex ID: W2607801531