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ToxSci Advance Access originally published online on April 27, 2005
Toxicological Sciences 2005 86(2):436-443; doi:10.1093/toxsci/kfi185
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Valproic Acid II: Effects on Oxidative Stress, Mitochondrial Membrane Potential, and Cytotoxicity in Glutathione-Depleted Rat Hepatocytes

Vincent Tong, Xiao Wei Teng, Thomas K. H. Chang and Frank S. Abbott1

Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3

Received March 11, 2005; accepted April 20, 2005

Oxidative stress has been associated with valproic acid (VPA) treatment, and mitochondrial dysfunction has been implicated in the pathogenesis of VPA-idiosyncratic hepatotoxicity. The present study investigated the effect of VPA and the role of GSH on oxidative stress, mitochondrial membrane potential, and toxicity in freshly isolated rat hepatocytes. Hepatocytes were isolated from Sprague-Dawley rats, and total levels of glutathione (GSH) reduced by pretreatment with a combination of L-buthionine sulfoximine (2 mM) and diethylmaleate (0.5 mM) prior to VPA (0–1000 µg/ml) treatment. Oxidative stress was determined by measuring the levels of 15-F2t-isoprostane (15-F2t-IsoP) and 2',7'-dichlorofluorescein (DCF). Mitochondrial membrane potential ({Delta}{psi}m) was determined by using the dual-fluorescent dye JC-1, and cell viability was evaluated by the water-soluble tetrazolium salt WST-1 assay. Exposure of rat hepatocytes to VPA (0–1000 µg/ml) resulted in a time- and dose-dependent increase in 15-F2t-IsoP and DCF fluorescence, and these levels were further elevated in GSH-reduced hepatocytes. In control hepatocytes, VPA had no effect on cell viability; however, significant cytotoxicity was observed in the glutathione-depleted hepatocytes treated with 1000 µg/ml VPA. The {Delta}{psi}m was only reduced in glutathione-reduced hepatocytes at 500 and 1000 µg/ml VPA. Our novel findings indicate that acute treatment of freshly isolated rat hepatocytes with VPA resulted in oxidative stress, which occurred in the absence of cytotoxicity, and that glutathione confers protection to hepatocytes against mitochondrial damage by VPA.

Key Words: Valproic acid; hepatocytes; 15-F2t-isoprostane; mitochondrial membrane potential; glutathione, 2',7'-dichlorofluorescein.


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