Metabolic activation of the new tricyclic antidepressant tianeptine by human liver cytochrome P450
| Autor: | Philippe Lettéron, Jacques Belghiti, Dominique Larrey, Marina Tinel, J. Loeper, Patrick Maurel, Dominique Pessayre |
|---|---|
| Rok vydání: | 1990 |
| Předmět: |
Quinidine
Piperonyl Butoxide Pyridines Metabolite Antidepressive Agents Tricyclic Dextromethorphan Biochemistry Troleandomycin chemistry.chemical_compound Cytochrome P-450 Enzyme System medicine Cytochrome P-450 Enzyme Inhibitors Humans Tianeptine Biotransformation Pharmacology chemistry.chemical_classification biology Cytochrome P450 Glutathione Isoenzymes Oxygen Enzyme chemistry Microsomes Liver Microsome biology.protein NADP medicine.drug |
| Zdroj: | Biochemical Pharmacology. 40:545-550 |
| ISSN: | 0006-2952 |
| Popis: | Incubation of [ 14 C]tianeptine (0.5 mM) with human liver microsomes and a NADPH-generating system resulted in the in vitro covalent binding of a tianeptine metabolite to microsomal proteins. This covalent binding required oxygen and NADPH. It was decreased by piperonyl butoxide (4mM) by 81%, and SKF 525-A (4mM) by 87%, two relatively non-specific inhibitors of cytochrome P450, and by glutathione (4mM) by 70%, a nucleophile. Covalent binding was decreased by 54% in the presence of troleandomycin (0.1 mM), a specific inhibitor of the glucocorticoid-inducible cytochrome P450 IIIA3, but remained unchanged in the presence of quinidine (0.1 mM) or dextromethorphan (0.1 mM), two inhibitors of cytochrome P450 IID6. Preincubation with IgG antibodies directed against cytochrome P450 IIIA3 decreased covalent binding by 65% whereas either preimmune IgG or IgG antibodies directed against P450 IA1, an isoenzyme inducible by polycyclic aromatic compounds, exhibited no significant inhibitory effect. We conclude that tianeptine is activated by human liver cytochrome P450 into a reactive metabolite. This activation is mediated in part by glucocorticoidinducible isoenzymes but not by P450 IID6 (the isoenzyme which oxidizes debrisoquine) nor by P450 IA1 (an isoenzyme inducible by polycyclic aromatic compounds). The predictive value of this study regarding possible idiosyncratic and immunoallergic reactions in humans remains unknown. |
| Databáze: | OpenAIRE |
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