MOLECULAR MECHANISM OF DICLOFENAC HEPATOTOXICITY - ASSOCIATION OF CELL INJURY WITH OXIDATIVE-METABOLISM AND DECREASE IN ATP LEVELS

A certain number of case reports of adverse hepatic reactions to diclo fenac are known, suggesting that diclofenac-associated hepatitis may b e more common than previously recognized. In order to discriminate amo ng possible molecular mechanisms of toxicity, the following were inves tigated: (a) cytotoxicity of diclofenac on metabolizing (rat hepatocyt es) acid non-metabolizing hepatic cells (HepG2, FaO); (b) changes in c alcium homoeostasis, glutathione (GSH), lipid peroxidation and ATP lev els, and (c) diclofenac metabolism in relation to cytotoxicity. The re sults indicate that toxicity is associated with the oxidative metaboli sm 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 decreas e in ATP levels. No oxidative stress (no changes in GSH, no lipid pero xidation) 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 dic lofenac hepatotoxicity.