JPET

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Fau, D.
Right arrow Articles by Pessayre, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Fau, D.
Right arrow Articles by Pessayre, D.

Mechanism for the hepatotoxicity of the antiandrogen, nilutamide. Evidence suggesting that redox cycling of this nitroaromatic drug leads to oxidative stress in isolated hepatocytes

D Fau, A Berson, D Eugene, B Fromenty, C Fisch and D Pessayre

Unite de Recherche de Physiopathologie Hepatique (INSERM U24), Hopital Beaujon, Clichy, France.

The nitroaromatic drug nilutamide has been shown previously to undergo redox cycling in aerobic rat liver microsomes, being reduced by NADPH- cytochrome P-450 reductase to a nitro anion-free radical which reacts with oxygen, to regenerate the parent drug, and form a superoxide anion dismuted to hydrogen peroxide. In the present study, the effects of nilutamide on isolated rat hepatocytes have been determined. After 6 and 8 hr of incubation with 0.5 mM nilutamide, lactate dehydrogenase was released in the incubation medium, and cell viability was decreased markedly. Consistent with a redox cycle producing reactive oxygen species, nilutamide increased nonmitochondrial (cyanide-resistant) oxygen consumption; the toxicity of nilutamide occurred sooner and was more extensive in the presence of sodium azide (an inhibitor of catalase). Consistent with an oxidative stress, the toxicity of nilutamide was associated with depletion of reduced glutathione, increased levels of glutathione disulfide, increased Ca(++)-dependent phosphorylase a activity, oxidation and accumulation of cytoskeleton- associated proteins and formation of blebs; toxicity was prevented by glutathione precursors, thiol reductants and/or antioxidants, such as L- cystine, L-cysteine, N-acetyl-L-cysteine, dithiothreitol, N,N'-diphenyl- p-phenylene-diamine and alpha-tocopherol. Feeding the animals with a diet supplemented with 2% L-cystine increased the initial glutathione stores of hepatocytes and prevented nilutamide toxicity. It is concluded that nilutamide is toxic to isolated rat hepatocytes, as a probable consequence of an oxidative stress due to the redox cycling of this nitroaromatic compound.

Volume 263, Issue 1, pp. 69-77, 10/01/1992
Copyright © 1992 by American Society for Pharmacology and Experimental Therapeutics




This article has been cited by other articles:


Home page
 J. Pharmacol. Exp. Ther.Home page
A. Berson, V. Descatoire, A. Sutton, D. Fau, B. Maulny, N. Vadrot, G. Feldmann, B. Berthon, T. Tordjmann, and D. Pessayre
Toxicity of Alpidem, a Peripheral Benzodiazepine Receptor Ligand, but Not Zolpidem, in Rat Hepatocytes: Role of Mitochondrial Permeability Transition and Metabolic Activation
J. Pharmacol. Exp. Ther., November 1, 2001; 299(2): 793 - 800.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 1992 by the American Society for Pharmacology and Experimental Therapeutics.