Ferbian Milas Siswanto, Maria Dara Novi Handayani, Rita Dewi Firmasyah, Ami Oguro, Susumu Imaoka
{"title":"Nrf2通过抑制Krüppel样因子9（KLF9）的活性来调节CYP2D6的表达。","authors":"Ferbian Milas Siswanto, Maria Dara Novi Handayani, Rita Dewi Firmasyah, Ami Oguro, Susumu Imaoka","doi":"10.2174/0113892002271342231013095255","DOIUrl":null,"url":null,"abstract":"<p><strong>Aims: </strong>The aim of the present study is to gain insight into the biology of Parkinson's disease (PD) and cancer to drive translational advances enabling more effective prevention and/or potential treatments.</p><p><strong>Background: </strong>The expression of Cytochrome P450 2D6 (CYP2D6) is correlated with various diseases such as PD and cancer; therefore, exploring its regulatory mechanism at transcriptional levels is of interest. NF-E2-related factor 2 (Nrf2) has been known to be responsible for regulating phase II and phase III drug-metabolizing genes.</p><p><strong>Objectives: </strong>The objectives of this study are to investigate the transcriptional regulation of <i>CYP2D6</i> by Nrf2 and to analyze its role in PD and cancer.</p><p><strong>Methods: </strong>Nrf2 was transiently expressed in human hepatoma Hep3B cells, and the expression of <i>CYP2D6</i> was examined by RT-qPCR. The promoter activity of <i>CYP2D6</i> and the DNA binding of Nrf2 were examined by luciferase and ChIP assay, respectively. We then investigated the expression and correlation of Nrf2 and <i>CYP2D6</i> in the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets.</p><p><strong>Results: </strong>In the present study, we demonstrated that Nrf2 down-regulated <i>CYP2D6</i> mRNA expression in hepatoma Hep3B cells. Mechanistically, Nrf2 binds to the antioxidant responsive element (ARE) in the proximity of krüppel- like factor 9 (KLF9)-binding site within the -550/+51 of <i>CYP2D6</i> promoter. The inhibition and activation of Nrf2 enhanced and suppressed KLF9 effects on <i>CYP2D6</i> expression, respectively. The expression levels of Nrf2 and <i>CYP2D6</i> were upregulated and downregulated in the PD patient GEO datasets compared to the healthy control tissues, and Nrf2 was negatively correlated with <i>CYP2D6</i>. In liver cancer patients, decreased <i>CYP2D6</i> levels were apparent and associated with a lower probability of survival.</p><p><strong>Conclusion: </strong>Our work revealed the inhibitory role of Nrf2 in regulating <i>CYP2D6</i> expression. Moreover, Nrf2- dependent regulation of <i>CYP2D6</i> can be used as a prognostic factor and therapeutic strategy in PD and liver cancer.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"667-681"},"PeriodicalIF":2.1000,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Nrf2 Regulates the Expression of <i>CYP2D6</i> by Inhibiting the Activity of Krüppel-Like Factor 9 (KLF9).\",\"authors\":\"Ferbian Milas Siswanto, Maria Dara Novi Handayani, Rita Dewi Firmasyah, Ami Oguro, Susumu Imaoka\",\"doi\":\"10.2174/0113892002271342231013095255\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Aims: </strong>The aim of the present study is to gain insight into the biology of Parkinson's disease (PD) and cancer to drive translational advances enabling more effective prevention and/or potential treatments.</p><p><strong>Background: </strong>The expression of Cytochrome P450 2D6 (CYP2D6) is correlated with various diseases such as PD and cancer; therefore, exploring its regulatory mechanism at transcriptional levels is of interest. NF-E2-related factor 2 (Nrf2) has been known to be responsible for regulating phase II and phase III drug-metabolizing genes.</p><p><strong>Objectives: </strong>The objectives of this study are to investigate the transcriptional regulation of <i>CYP2D6</i> by Nrf2 and to analyze its role in PD and cancer.</p><p><strong>Methods: </strong>Nrf2 was transiently expressed in human hepatoma Hep3B cells, and the expression of <i>CYP2D6</i> was examined by RT-qPCR. The promoter activity of <i>CYP2D6</i> and the DNA binding of Nrf2 were examined by luciferase and ChIP assay, respectively. We then investigated the expression and correlation of Nrf2 and <i>CYP2D6</i> in the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets.</p><p><strong>Results: </strong>In the present study, we demonstrated that Nrf2 down-regulated <i>CYP2D6</i> mRNA expression in hepatoma Hep3B cells. Mechanistically, Nrf2 binds to the antioxidant responsive element (ARE) in the proximity of krüppel- like factor 9 (KLF9)-binding site within the -550/+51 of <i>CYP2D6</i> promoter. The inhibition and activation of Nrf2 enhanced and suppressed KLF9 effects on <i>CYP2D6</i> expression, respectively. The expression levels of Nrf2 and <i>CYP2D6</i> were upregulated and downregulated in the PD patient GEO datasets compared to the healthy control tissues, and Nrf2 was negatively correlated with <i>CYP2D6</i>. In liver cancer patients, decreased <i>CYP2D6</i> levels were apparent and associated with a lower probability of survival.</p><p><strong>Conclusion: </strong>Our work revealed the inhibitory role of Nrf2 in regulating <i>CYP2D6</i> expression. 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Nrf2 Regulates the Expression of CYP2D6 by Inhibiting the Activity of Krüppel-Like Factor 9 (KLF9).
Aims: The aim of the present study is to gain insight into the biology of Parkinson's disease (PD) and cancer to drive translational advances enabling more effective prevention and/or potential treatments.
Background: The expression of Cytochrome P450 2D6 (CYP2D6) is correlated with various diseases such as PD and cancer; therefore, exploring its regulatory mechanism at transcriptional levels is of interest. NF-E2-related factor 2 (Nrf2) has been known to be responsible for regulating phase II and phase III drug-metabolizing genes.
Objectives: The objectives of this study are to investigate the transcriptional regulation of CYP2D6 by Nrf2 and to analyze its role in PD and cancer.
Methods: Nrf2 was transiently expressed in human hepatoma Hep3B cells, and the expression of CYP2D6 was examined by RT-qPCR. The promoter activity of CYP2D6 and the DNA binding of Nrf2 were examined by luciferase and ChIP assay, respectively. We then investigated the expression and correlation of Nrf2 and CYP2D6 in the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets.
Results: In the present study, we demonstrated that Nrf2 down-regulated CYP2D6 mRNA expression in hepatoma Hep3B cells. Mechanistically, Nrf2 binds to the antioxidant responsive element (ARE) in the proximity of krüppel- like factor 9 (KLF9)-binding site within the -550/+51 of CYP2D6 promoter. The inhibition and activation of Nrf2 enhanced and suppressed KLF9 effects on CYP2D6 expression, respectively. The expression levels of Nrf2 and CYP2D6 were upregulated and downregulated in the PD patient GEO datasets compared to the healthy control tissues, and Nrf2 was negatively correlated with CYP2D6. In liver cancer patients, decreased CYP2D6 levels were apparent and associated with a lower probability of survival.
Conclusion: Our work revealed the inhibitory role of Nrf2 in regulating CYP2D6 expression. Moreover, Nrf2- dependent regulation of CYP2D6 can be used as a prognostic factor and therapeutic strategy in PD and liver cancer.
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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