Sertraline-induced potentiation of the CYP3A4-dependent neurotoxicity of carbamazepine: An in vitro study

Chaitali Ghosh, Mohammad Hossain, Addison Spriggs, Arnab Ghosh, Gerald A. Grant, Nicola Marchi, Emilio Perucca, Damir Janigro

Research output: Contribution to journalArticle

13 Citations (Scopus)

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. Significance 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.

Original languageEnglish
Pages (from-to)439-449
Number of pages11
JournalEpilepsia
Volume56
Issue number3
DOIs
Publication statusPublished - Mar 1 2015

Fingerprint

Sertraline
Cytochrome P-450 CYP3A
Carbamazepine
Endothelial Cells
Brain
Nitrites
Kidney
Cytochrome P-450 Enzyme System
In Vitro Techniques
Pharmaceutical Preparations
Ketoconazole
Dopaminergic Neurons
Serotonin Uptake Inhibitors
Biotransformation
Drug-Related Side Effects and Adverse Reactions
Anticonvulsants
Free Radicals
Glutathione
Cysteine
Epilepsy

Keywords

  • CYP3A4
  • Cytotoxicity
  • Drug interaction
  • Human
  • Ketoconazole
  • Neurotoxicity

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

Cite this

Ghosh, C., Hossain, M., Spriggs, A., Ghosh, A., Grant, G. A., Marchi, N., ... Janigro, D. (2015). Sertraline-induced potentiation of the CYP3A4-dependent neurotoxicity of carbamazepine: An in vitro study. Epilepsia, 56(3), 439-449. https://doi.org/10.1111/epi.12923

Sertraline-induced potentiation of the CYP3A4-dependent neurotoxicity of carbamazepine : An in vitro study. / Ghosh, Chaitali; Hossain, Mohammad; Spriggs, Addison; Ghosh, Arnab; Grant, Gerald A.; Marchi, Nicola; Perucca, Emilio; Janigro, Damir.

In: Epilepsia, Vol. 56, No. 3, 01.03.2015, p. 439-449.

Research output: Contribution to journalArticle

Ghosh, C, Hossain, M, Spriggs, A, Ghosh, A, Grant, GA, Marchi, N, Perucca, E & Janigro, D 2015, 'Sertraline-induced potentiation of the CYP3A4-dependent neurotoxicity of carbamazepine: An in vitro study', Epilepsia, vol. 56, no. 3, pp. 439-449. https://doi.org/10.1111/epi.12923
Ghosh, Chaitali ; Hossain, Mohammad ; Spriggs, Addison ; Ghosh, Arnab ; Grant, Gerald A. ; Marchi, Nicola ; Perucca, Emilio ; Janigro, Damir. / Sertraline-induced potentiation of the CYP3A4-dependent neurotoxicity of carbamazepine : An in vitro study. In: Epilepsia. 2015 ; Vol. 56, No. 3. pp. 439-449.
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N2 - 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. Significance 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.

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