title: Effect of status epilepticus and antiepileptic drugs on CYP2E1 brain expression.
abstract: P450 metabolic enzymes are expressed in the human and rodent brain. Recent data support their involvement in the pathophysiology of epilepsy. However, the determinants of metabolic enzyme expression in the epileptic brain are unclear. We tested the hypothesis that status epilepticus (SE) or exposure to phenytoin or phenobarbital affects brain expression of the metabolic enzyme CYP2E1. SE was induced in C57BL/6J mice by systemic kainic acid. Brain CYP2E1 expression was evaluated 18-24h after severe SE by immunohistochemistry. Co-localization with neuronal nuclei (NEUN), glial fibrillary acidic protein (GFAP) and CD31 was determined by confocal microscopy. The effect of phenytoin, carbamazepine and phenobarbital on CYP2E1 expression was evaluated in vivo or by using organotypic hippocampal cultures in vitro. CYP2E1 expression was investigated in brain resections from a cohort of drug-resistant epileptic brain resections and human endothelial cultures (EPI-EC). Immunohistochemistry showed an increase of CYP2E1 expression limited to hippocampal CA2/3 and hilar neurons after severe SE in mice. CYP2E1 expression was also observed at the astrocyte-vascular interface. Analysis of human brain specimens revealed CYP2E1 expression in neurons and vascular endothelial cells (EC). CYP2E1 was expressed in cultured human EC and over-expressed by EPI-EC. When analyzing the effect of drug exposure on CYP2E1 expression we found that, in vivo or in vitro, ethanol increased CYP2E1 levels in the brain and liver. Treatment with phenytoin induced localized CYP2E1 expression in the brain whereas no significant effects were exerted by carbamazepine or phenobarbital. Our data indicate that the effect of acute SE on brain CYP2E1 expression is localized and cell specific. Exposure to selected anti-epileptic drugs could play a role in determining CYP2E1 brain expression. Additional investigation is required to fully reproduce the culprits of P450 enzyme expression as observed in the human epileptic brain.
authors.affiliation: Laboratory of Cerebrovascular Mechanisms of Brain Disorders, Department of Neuroscience, Institute of Functional Genomics, Centre National Recherche Scientifique (CNRS), Montpellier, France.
authors.forename: B
authors.initials: B
authors.lastname: Boussadia
authors.affiliation: Cerebrovascular Research Center, Department of Biomedical Engineering and Molecular Medicine, Cleveland Clinic, USA.
authors.forename: C
authors.initials: C
authors.lastname: Ghosh
authors.affiliation: Laboratory of Cerebrovascular Mechanisms of Brain Disorders, Department of Neuroscience, Institute of Functional Genomics, Centre National Recherche Scientifique (CNRS), Montpellier, France.
authors.forename: C
authors.initials: C
authors.lastname: Plaud
authors.affiliation: Laboratory of Signaling, Plasticity and Cancer, Department of Cancer Biology, Institute of Functional Genomics, Centre National Recherche Scientifique (CNRS), Montpellier, France.
authors.forename: J M
authors.initials: JM
authors.lastname: Pascussi
authors.affiliation: Laboratory of Cerebrovascular Mechanisms of Brain Disorders, Department of Neuroscience, Institute of Functional Genomics, Centre National Recherche Scientifique (CNRS), Montpellier, France.
authors.forename: F
authors.initials: F
authors.lastname: de Bock
authors.affiliation: Laboratory of Cerebrovascular Mechanisms of Brain Disorders, Department of Neuroscience, Institute of Functional Genomics, Centre National Recherche Scientifique (CNRS), Montpellier, France.
authors.forename: M C
authors.initials: MC
authors.lastname: Rousset
authors.affiliation: Cerebrovascular Research Center, Department of Biomedical Engineering and Molecular Medicine, Cleveland Clinic, USA. Electronic address: janigrd@ccf.org.
authors.forename: D
authors.initials: D
authors.lastname: Janigro
authors.affiliation: Laboratory of Cerebrovascular Mechanisms of Brain Disorders, Department of Neuroscience, Institute of Functional Genomics, Centre National Recherche Scientifique (CNRS), Montpellier, France. Electronic address: nicola.marchi@igf.cnrs.fr.
authors.forename: N
authors.initials: N
authors.lastname: Marchi
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002220:Carbamazepine / Q000494:pharmacology; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D002675:Child, Preschool; D019392:Cytochrome P-450 CYP2E1 / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism*; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D010672:Phenytoin / Q000494:pharmacology*; D013226:Status Epilepticus / Q000378:metabolism*
chemical_list: D000927:Anticonvulsants; D002492:Central Nervous System Depressants; D002220:Carbamazepine; D000431:Ethanol; D010672:Phenytoin; D019392:Cytochrome P-450 CYP2E1; D010634:Phenobarbital
keywords: CYP2E1; biotransformation; drug exposure; status epilepticus