Pregnenolone 16α-carbonitrile negatively regulates hippocampal cytochrome P450 enzymes and ameliorates phenytoin-induced hippocampal neurotoxicity  

作　　者：Shuai Zhang Tingting Wang Ye Feng Fei Li Aijuan Qu Xiuchen Guan Hui Wang Dan Xu 

机构地区：[1]Department of Obstetric,Zhongnan Hospital of Wuhan University,School of Pharmaceutical Sciences,Wuhan University,Wuhan,430071,China [2]Department of Pharmacology,School of Basic Medical Sciences,Wuhan University,Wuhan,430071,China [3]Hubei Provincial Key Laboratory of Developmentally Originated Disease,Wuhan University,Wuhan,430071,China [4]Department of Endocrinology and Metabolic Disease,The First Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou,310058,China [5]Frontiers Science Center for Disease-related Molecular Network,West China Hospital,Sichuan University,Chengdu,610041,China [6]Department of Physiology and Pathophysiology,School of Basic Medical Sciences,Capital Medical University,Beijing,100069,China [7]Key Laboratory of Remodeling-related Cardiovascular Diseases,Ministry of Education,Beijing,100069,China [8]Department of Orthodontics,School of Stomatology,Capital Medical University,Beijing,100069,China

出　　处：《Journal of Pharmaceutical Analysis》2023年第12期1510-1525,共16页药物分析学报（英文版）

基　　金：supported in part by grants from the National Natural Science Foundation of China(Grant Nos.:81973405,82122071,and 82030111)to Dan Xu;Hui Wang,the National Key R&D Program of China(Grant No.:2020YFA0803900)to Hui Wang;the Hubei Provincial Natural Science Foundation Outstanding Youth Found,China(Grant No.:2022CFA083).

摘　　要：The central nervous system is susceptible to the modulation of various neurophysiological processes by the cytochrome P450 enzyme(CYP),which plays a crucial role in the metabolism of neurosteroids.The antiepileptic drug phenytoin(PHT)has been observed to induce neuronal side effects in patients,which could be attributed to its induction of CYP expression and testosterone(TES)metabolism in the hippocampus.While pregnane X receptor(PXR)is widely known for its regulatory function of CYPs in the liver,we have discovered that the treatment of mice with pregnenolone 16α-carbonitrile(PCN),a PXR agonist,has differential effects on CYP expression in the liver and hippocampus.Specifically,the PCN treatment resulted in the induction of cytochrome P450,family 3,subfamily a,polypeptide 11(CYP3A11),and CYP2B10 expression in the liver,while suppressing their expression in the hippocampus.Functionally,the PCN treatment protected mice from PHT-induced hippocampal nerve injury,which was accompanied by the inhibition of TES metabolism in the hippocampus.Mechanistically,we found that the inhibition of hippocampal CYP expression and attenuation of PHT-induced neurotoxicity by PCN were glucocorticoid receptor dependent,rather than PXR independent,as demonstrated by genetic and pharmacological models.In conclusion,our study provides evidence that PCN can negatively regulate hippocampal CYP expression and attenuate PHT-induced hippocampal neurotoxicity independently of PXR.Our findings suggest that glucocorticoids may be a potential therapeutic strategy for managing the neuronal side effects of PHT.

关 键 词：Pregnenolone 16a-carbonitrile Pregnane X receptor Hippocampus Glucocorticoid receptor Phenytoin sodium NEUROTOXICITY 

分 类 号：R96[医药卫生—药理学]