PMID: 20650110Aug 1, 1995Paper

Molecular mechanism of diclofenac hepatotoxicity: Association of cell injury with oxidative metabolism and decrease in ATP levels

Toxicology in Vitro : an International Journal Published in Association with BIBRA
Xavier PonsodaJosé V Castell

Abstract

A certain number of case reports of adverse hepatic reactions to diclofenac are known, suggesting that diclofenac-associated hepatitis may be more common than previously recognized. In order to discriminate among possible molecular mechanisms of toxicity, the following were investigated: (a) cytotoxicity of diclofenac on metabolizing (rat hepatocytes) and non-metabolizing hepatic cells (HepG2, FaO); (b) changes in calcium homoeostasis, glutathione (GSH), lipid peroxidation and ATP levels, and (c) diclofenac metabolism in relation to cytotoxicity. The results indicate that toxicity is associated with the oxidative metabolism of the drug, and correlated with the formation of a minor oxidation metabolite. Inhibitors of diclofenac metabolism concomitantly reduced the toxicity of the drug. Hepatocyte injury was preceded by a decrease in ATP levels. No oxidative stress (no changes in GSH, no lipid peroxidation) could be demonstrated at this early stage. Cytotoxicity was prevented when cells were incubated with fructose, suggesting that the inability of mitochondria to produce ATP is the probable cause of diclofenac hepatotoxicity.

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Citations

Oct 25, 2003·Toxicology and Applied Pharmacology·Urs A Boelsterli
Nov 6, 2003·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Maria-José Gómez-LechónJosé V Castell
Oct 1, 1997·Toxicology in Vitro : an International Journal Published in Association with BIBRA·R Gebhardt, M Fausel
Mar 29, 2012·Toxicological Sciences : an Official Journal of the Society of Toxicology·Stephen J Fey, Krzysztof Wrzesinski
Mar 4, 2014·The American Journal of Emergency Medicine·Sahin ColakAyhan Saritas
Jan 18, 2013·Drug Safety : an International Journal of Medical Toxicology and Drug Experience·Sinem Ezgi GulmezNicholas Moore
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Dec 1, 2006·Chemico-biological Interactions·María José Gómez-LechónMaría Teresa Donato
Jul 11, 2006·Toxicology and Applied Pharmacology·Jinsheng Xu, Wendy M Purcell
Apr 12, 2015·Toxicology in Vitro : an International Journal Published in Association with BIBRA·D Dias-da-SilvaH Carmo
Jul 12, 2014·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Xiaoyu NiuGeny M M Groothuis
Dec 17, 2003·Water Research·Davide VognaMarco d'Ischia
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Mar 2, 2021·Physiological Research·M NemcovaV Seidlova
Mar 19, 2021·Frontiers in Cell and Developmental Biology·Ana S SerrasJoana P Miranda

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