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Vol. 288, Issue 1, 65-72, January 1999
Unidad de Hepatología Experimental, Centro de
Investigación, Hospital Universitario "La Fe", Valencia,
Spain (R.J., M.J.G.-L., R.B., J.V.C.);
Departamento de
Bioquímica, Facultad de Medicina, Universidad de Valencia,
Valencia, Spain (R.B., R.J., J.V.C.); and
Departamento de
Parasitología y Biología Celular, Facultad de Ciencias
Biológicas, Universidad de Valencia, Valencia, Spain (X.P.)
Diclofenac, a 2-arylacetic acid, nonsteroidal anti-inflammatory drug,
has been reported to cause adverse hepatic effects in certain
individuals. To discriminate among possible mechanisms of
hepatotoxicity, we examined the effects of diclofenac on human and rat
hepatocytes and hepatic cell lines (HepG2, FaO), investigated the major
biochemical events in the course of diclofenac cytotoxicity (calcium
homeostasis, lipid peroxidation, and mitochondrial dysfunction), and
investigated whether cytotoxicity could be related to drug metabolism
by cytochrome P-450. Acute diclofenac-induced toxicity in hepatocytes
was preluded by a decrease in ATP levels, whereas no significant
oxidative stress (decrease in glutathione and lipid peroxidation) or
increase in intracellular calcium concentration could be observed at
early incubation stages. Diclofenac was more cytotoxic to drug
metabolizing cells (rat and human primary cultured hepatocytes) than to
nonmetabolizing cell lines (HepG2, FaO). Despite the fact that
diclofenac itself was effective in impairing ATP synthesis by
mitochondria, we found evidence that toxicity was also related to drug
metabolism and was reduced by the addition of cytochrome P-450
inhibitors (proadifen and ketoconazole) to culture medium. The in vitro
cytotoxicity correlated well with the formation by hepatocytes of
5-hydroxydiclofenac and, in particular, N,5-dihydroxydiclofenac, a minor metabolite first
characterized in this article. Hepatic microsomes showed the ability to
both oxidize 5-hydroxydiclofenac to
N,5-dihydroxydiclofenac and back reduce the latter to
5-hydroxydiclofenac with the consumption of NADPH. The experimental
results suggest that the toxic effect of diclofenac on hepatocytes may
be caused by drug-induced mitochondrial impairment, together with a
futile consumption of NADPH.
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