title: Sertraline-induced potentiation of the CYP3A4-dependent neurotoxicity of carbamazepine: an in vitro study.
abstract: OBJECTIVE
  Drug toxicity is a hurdle to drug development and to clinical translation of basic research. Antiepileptic drugs such as carbamazepine (CBZ) and selective serotonin reuptake inhibitors such as sertraline (SRT) are commonly co-prescribed to patients with epilepsy and comorbid depression. Because SRT may interfere with cytochrome P450 (CYP) enzyme activity and CYPs have been implicated in the conversion of CBZ to reactive cytotoxic metabolites, we investigated in vitro models to determine whether SRT affects the neurotoxic potential of CBZ and the mechanisms involved.
  
  
  METHODS
  Human fetal brain-derived dopaminergic neurons, human brain microvascular endothelial cells (HBMECs), and embryonic kidney (HEK) cells were used to evaluate cytotoxicity of CBZ and SRT individually and in combination. Nitrite and glutathione (GSH) levels were measured with drug exposure. To validate the role of CYP3A4 in causing neurotoxicity, drug metabolism was compared to cell death in HEK CYP3A4 overexpressed and cells pretreated with the CYP3A4 inhibitor ketoconazole.
  
  
  RESULTS
  In all cellular systems tested, exposure to CBZ (127 μM) or SRT (5 μM) alone caused negligible cytotoxicity. By contrast CBZ, tested at a much lower concentration (17 μM) in combination with SRT (5 μM), produced prominent cytotoxicity within 15 min exposure. In neurons and HBMECs, cytotoxicity was associated with increased nitrite levels, suggesting involvement of free radicals as a pathogenetic mechanism. Pretreatment of HBMECs with reduced GSH or with the GSH precursor N-acetyl-L-cysteine prevented cytotoxic response. In HEK cells, the cytotoxic response to the CBZ + SRT combination correlated with the rate of CBZ biotransformation and production of 2-hydroxy CBZ, further suggesting a causative role of reactive metabolites. In the same system, cytotoxicity was potentiated by overexpression of CYP3A4, and prevented by CYP3A4 inhibitor.
  
  
  CONCLUSIONS
  These results demonstrate an unexpected neurotoxic interaction between CBZ and SRT, apparently related to increased CYP3A4-mediated production of reactive CBZ metabolites. The potential clinical implications of these findings are discussed.
authors: Cerebrovascular Research, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, U.S.A; Department of Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, U.S.A; Department of Bio-medical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, U.S.A.
authors: Chaitali
authors: C
authors: Ghosh
authors: Mohammad
authors: M
authors: Hossain
authors: Addison
authors: A
authors: Spriggs
authors: Arnab
authors: A
authors: Ghosh
authors: Gerald A
authors: GA
authors: Grant
authors: Nicola
authors: N
authors: Marchi
authors: Emilio
authors: E
authors: Perucca
authors: Damir
authors: D
authors: Janigro
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000263:Adenylate Kinase / Q000378:metabolism; D000927:Anticonvulsants / Q000633:toxicity*; D001921:Brain / Q000166:cytology; D002220:Carbamazepine / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects*; D005333:Fetus; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects; D009573:Nitrites / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D020280:Sertraline / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000111:Acetylcysteine; D000263:Adenylate Kinase; D000927:Anticonvulsants; D002220:Carbamazepine; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D005978:Glutathione; D007654:Ketoconazole; D009573:Nitrites; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline
keywords: CYP3A4; Cytotoxicity; Drug interaction; Human; Ketoconazole; Neurotoxicity
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