Metabolism-dependent stimulation of reactive oxygen species and DNA synthesis by cyclosporin A in rat smooth muscle cells.

Détails

ID Serval
serval:BIB_10336
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Metabolism-dependent stimulation of reactive oxygen species and DNA synthesis by cyclosporin A in rat smooth muscle cells.
Périodique
Free Radical Biology and Medicine
Auteur⸱e⸱s
Nguyen N.S., Cottet-Maire F., Buetler T.M., Lo Russo A., Krauskopf A.S., Armstrong J.M., Vickers A.E., Macé K., Rüegg U.T.
ISSN
0891-5849 (Print)
ISSN-L
0891-5849
Statut éditorial
Publié
Date de publication
1999
Volume
27
Numéro
11-12
Pages
1267-1275
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
The clinical use of the immunosuppressive drug cyclosporin A (CsA) is limited by its side effects, namely hypertension and nephrotoxicity. It has been proposed that reactive oxygen species (ROS) could be involved as mediators of the toxic effects of CsA. Here, we have studied the possible interrelationship between CsA metabolism and production of ROS. Using cultures of rat aortic smooth muscle cells (RASMC), CsA (1 microM) produced a rapid (within 10 min) increase in reactive oxygen species, detected by oxidation of the fluorescent probes 2,7-dichlorofluorescin and dihydrorhodamine-123. DNA synthesis was increased in the presence of CsA as assessed by [3H]thymidine incorporation. The superoxide dismutase inhibitor diethyldithiocarbamate (1 mM) and the iron chelator desferal (5 microM), as well as ketoconazole (1 microM) and troleandomycin (10 microM), inhibitors of the cytochrome P-450 3A, were able to block both effects. High-performance liquid chromatography analysis revealed that RASMC were capable to metabolize CsA to its primary metabolites (AM1, AM9 and AM4N), and that their formation was inhibited by ketoconazole and troleandomycin. Furthermore, mRNAs encoding cytochrome P-450 3A1 and 3A2 were detected in RASMC by reverse transcriptase-polymerase chain reaction. Our data suggest that CsA is metabolized by cytochrome P-450 3A in RASMC producing reactive oxygen species, most likely superoxide and the hydroxyl radical, known to damage lipids and DNA.
Mots-clé
Animals, Aorta, Aryl Hydrocarbon Hydroxylases, Chelating Agents/pharmacology, Chromatography, High Pressure Liquid, Cyclosporine/metabolism, Cyclosporine/pharmacology, Cytochrome P-450 CYP3A, Cytochrome P-450 Enzyme System/antagonists & inhibitors, Cytochrome P-450 Enzyme System/genetics, DNA/biosynthesis, Deferoxamine/pharmacology, Ditiocarb/pharmacology, Enzyme Inhibitors/pharmacology, Fluorescent Dyes, Male, Muscle, Smooth, Vascular/chemistry, Muscle, Smooth, Vascular/drug effects, Oxidation-Reduction, Oxidoreductases, N-Demethylating/antagonists & inhibitors, Oxidoreductases, N-Demethylating/genetics, Protein Kinase C/metabolism, RNA, Messenger/analysis, Rats, Rats, Inbred WKY, Reactive Oxygen Species/metabolism
Pubmed
Création de la notice
19/11/2007 9:29
Dernière modification de la notice
20/08/2019 12:37
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