Status Epilepticus Decreases Brain Cytochrome P450 2D4 Expression in Rats

Abstract

Status epilepticus (SE) is a life-threatening neurological emergency characterized by frequent seizures. The present study aims at elucidating the effect of SE on CYP2D4 expression in the rat brain. To create a rat model of SE, Sprague-Dawley rats were intraperitoneally administered 10 mg/kg kainic acid. The CYP2D4 mRNA levels in the cortex and hippocampus of the SE rats were decreased by 0.38- and 0.39-fold, respectively. The protein level of octamer transcription factor 1 (Oct-1), which is involved in the transcriptional activation of CYP2D4 by binding to the CYP2D4 regulatory element, was also attenuated by 0.64- and 0.51-fold in these regions of the SE rat, suggesting that a reduction in Oct-1 may be involved in the CYP2D4 suppression. Yin yang 1 can function as a cofactor of histone deacetylase 1 and inhibit the binding of Oct-1 to the CYP2D4 regulatory element. The coimmunoprecipitation assay revealed that the interaction between yin yang 1 and histone deacetylase 1 in the cortex and hippocampus was enhanced during SE, indicating that this interaction is also responsible for the CYP2D4 suppression. This study clarified that SE led to a decrease in the expression of CYP2D4, thus altering the pharmacokinetics and efficacy of the drugs in the brain.