title: Metabolic activation of the new tricyclic antidepressant tianeptine by human liver cytochrome P450.
abstract: Incubation of [14C]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 (4 mM) by 81%, and SKF 525-A (4 mM) by 87%, two relatively non-specific inhibitors of cytochrome P450, and by glutathione (4 mM) 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 glucocorticoid-inducible 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.
authors.affiliation: Unité de Recherches de Physiopathologie Hépatique (INSERM U 24), Hôpital Beaujon, Clichy, France.
authors.forename: D
authors.initials: D
authors.lastname: Larrey
authors.forename: M
authors.initials: M
authors.lastname: Tinel
authors.forename: P
authors.initials: P
authors.lastname: Lettéron
authors.forename: P
authors.initials: P
authors.lastname: Maurel
authors.forename: J
authors.initials: J
authors.lastname: Loeper
authors.forename: J
authors.initials: J
authors.lastname: Belghiti
authors.forename: D
authors.initials: D
authors.lastname: Pessayre
mesh_terms: D000929:Antidepressive Agents, Tricyclic / Q000378:metabolism*; D001711:Biotransformation; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003915:Dextromethorphan / Q000494:pharmacology; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D009249:NADP / Q000378:metabolism; D010100:Oxygen / Q000494:pharmacology; D010882:Piperonyl Butoxide / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011802:Quinidine / Q000494:pharmacology; D014217:Troleandomycin / Q000494:pharmacology
chemical_list: D000929:Antidepressive Agents, Tricyclic; D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D011725:Pyridines; C013109:metapyrone; D009249:NADP; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; D014217:Troleandomycin; D005978:Glutathione; D011802:Quinidine; D010882:Piperonyl Butoxide; D010100:Oxygen