Status Epilepticus Decreases Brain Cytochrome P450 2D4 Expression in Rats
Status Epilepticus Decreases Brain Cytochrome P450 2D4 Expression in Rats
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DOI：
10.1016/j.xphs.2017.11.010
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发表时间：
2018-04-01
影响因子：
3.8
通讯作者：
Katoh, Miki
中科院分区：
文献类型：
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作者：
Asai, Yuki;Tanaka, Hatsuna;Katoh, Miki
癫痫持续状态（SE）是一种以频繁发作为特征的危及生命的神经系统急症。本研究旨在阐明SE对大鼠脑组织中CYP2D4表达的影响。为了建立SE大鼠模型，Sprague-Dawley大鼠腹腔注射kainic酸10 mg/kg。SE大鼠皮层和海马中CYP2D4 mRNA水平分别下降0.38倍和0.39倍。通过结合CYP2D4调控元件参与CYP2D4转录激活的八聚体转录因子1 （Oct-1）的蛋白水平在SE大鼠的这些区域也降低了0.64倍和0.51倍，这表明Oct-1的降低可能参与了CYP2D4的抑制。阴阳1可以作为组蛋白去乙酰化酶1的辅助因子，抑制Oct-1与CYP2D4调控元件的结合。共免疫沉淀实验显示，在SE期间，皮层和海马中阴阳1与组蛋白去乙酰化酶1的相互作用增强，表明这种相互作用也是CYP2D4抑制的原因。本研究阐明了SE导致CYP2D4表达降低，从而改变药物在脑内的药代动力学和疗效。(C) 2018美国药剂师协会(R)。Elsevier Inc.出版。版权所有。
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. (C) 2018 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.