{"title":"Inhibition of <i>Glycyrrhiza</i> Polysaccharide on Human Cytochrome P450 46A1 <i>in vitro</i> and <i>in vivo</i>: Implications in Treating Neurological Diseases.","authors":"Jie Du, Zujia Chen, Xiaodong Chen, Jiahui Zhang, Yaojun Wang, Tingting Zhao, Dalong Wang, Changyuan Wang, Yanwei Chen, Qiang Meng, Huijun Sun, Kexin Liu, Jingjing Wu","doi":"10.2174/0113892002305873240520072802","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Cytochrome P450 (CYP) 46A1, also known as cholesterol 24S-hydroxylase, is essential for maintaining the homeostasis of cholesterol in the brain and serves as a therapeutic target of neurodegenerative disorders and excitatory neurotoxicity. N-methyl-d-aspartate receptor (NMDAR) is a prototypical receptor for the excitatory neurotransmitter glutamate and can be specifically regulated by 24S-hydroxycholesterol (24S-HC). Glycyrrhiza is one of the most widely used herbs with broad clinical applications, which has several pharmacological activities, such as clearing heat and detoxifying, moistening the lung and relieving cough, analgesic, neuroprotective outcomes, and regulating a variety of drug activities. Glycyrrhiza is a commonly used herb for the treatment of epileptic encephalopathy. However, whether glycyrrhiza can interfere with the activity of CYP46A1 remains unknown.</p><p><strong>Objective: </strong>This study aimed to investigate the regulating effects of glycyrrhiza polysaccharides (GP) on CYP46A1-mediated cholesterol conversion, as well as in the modulation of related proteins.</p><p><strong>Materials and methods: </strong>The effects of glycyrrhiza polysaccharide (GP) on the activity of CYP46A1 were investigated <i>in vivo</i> and <i>in vitro</i>. Moreover, the potential regulatory effects of GP on the expressions of CYP46A1, HMG-CoA reductase (HMGCR), and NMDAR were also detected.</p><p><strong>Results: </strong>The <i>in vitro</i> results demonstrated that glycyrrhiza polysaccharide (GP), as the main water-soluble active component of glycyrrhiza, remarkably inhibited the activity of CYP46A1 in a non-competitive mode with a Ki value of 0.7003 mg/ml. Furthermore, the <i>in vivo</i> experiments verified that GP markedly decreased the contents of 24S-HC in rat plasma and brain tissues as compared to the control. More importantly, the protein expressions of CYP46A1, GluN2A, GluN2B, and HMG-CoA reductase (HMGCR) in rat brains were all downregulated, whereas the mRNA expressions of CYP46A1 and HMGCR were not significantly changed after treatment with GP.</p><p><strong>Conclusion: </strong>GP exhibits a significant inhibitory effect on CYP46A1 activity <i>in vitro</i> and <i>in vivo</i>, and the protein expressions of CYP46A1, HMGCR, and NMDAR are also inhibited by GP, which are of considerable clinical significance for GP's potential therapeutic role in treating neurological diseases.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":null,"pages":null},"PeriodicalIF":2.1000,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Current drug metabolism","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2174/0113892002305873240520072802","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Cytochrome P450 (CYP) 46A1, also known as cholesterol 24S-hydroxylase, is essential for maintaining the homeostasis of cholesterol in the brain and serves as a therapeutic target of neurodegenerative disorders and excitatory neurotoxicity. N-methyl-d-aspartate receptor (NMDAR) is a prototypical receptor for the excitatory neurotransmitter glutamate and can be specifically regulated by 24S-hydroxycholesterol (24S-HC). Glycyrrhiza is one of the most widely used herbs with broad clinical applications, which has several pharmacological activities, such as clearing heat and detoxifying, moistening the lung and relieving cough, analgesic, neuroprotective outcomes, and regulating a variety of drug activities. Glycyrrhiza is a commonly used herb for the treatment of epileptic encephalopathy. However, whether glycyrrhiza can interfere with the activity of CYP46A1 remains unknown.
Objective: This study aimed to investigate the regulating effects of glycyrrhiza polysaccharides (GP) on CYP46A1-mediated cholesterol conversion, as well as in the modulation of related proteins.
Materials and methods: The effects of glycyrrhiza polysaccharide (GP) on the activity of CYP46A1 were investigated in vivo and in vitro. Moreover, the potential regulatory effects of GP on the expressions of CYP46A1, HMG-CoA reductase (HMGCR), and NMDAR were also detected.
Results: The in vitro results demonstrated that glycyrrhiza polysaccharide (GP), as the main water-soluble active component of glycyrrhiza, remarkably inhibited the activity of CYP46A1 in a non-competitive mode with a Ki value of 0.7003 mg/ml. Furthermore, the in vivo experiments verified that GP markedly decreased the contents of 24S-HC in rat plasma and brain tissues as compared to the control. More importantly, the protein expressions of CYP46A1, GluN2A, GluN2B, and HMG-CoA reductase (HMGCR) in rat brains were all downregulated, whereas the mRNA expressions of CYP46A1 and HMGCR were not significantly changed after treatment with GP.
Conclusion: GP exhibits a significant inhibitory effect on CYP46A1 activity in vitro and in vivo, and the protein expressions of CYP46A1, HMGCR, and NMDAR are also inhibited by GP, which are of considerable clinical significance for GP's potential therapeutic role in treating neurological diseases.
期刊介绍：
Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism, pharmacokinetics, and drug disposition. The journal serves as an international forum for the publication of full-length/mini review, research articles and guest edited issues in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the most important developments. The journal covers the following general topic areas: pharmaceutics, pharmacokinetics, toxicology, and most importantly drug metabolism.
More specifically, in vitro and in vivo drug metabolism of phase I and phase II enzymes or metabolic pathways; drug-drug interactions and enzyme kinetics; pharmacokinetics, pharmacokinetic-pharmacodynamic modeling, and toxicokinetics; interspecies differences in metabolism or pharmacokinetics, species scaling and extrapolations; drug transporters; target organ toxicity and interindividual variability in drug exposure-response; extrahepatic metabolism; bioactivation, reactive metabolites, and developments for the identification of drug metabolites. Preclinical and clinical reviews describing the drug metabolism and pharmacokinetics of marketed drugs or drug classes.
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