2021/04/08 更新

写真a

コダマ ススム
児玉 進
KODAMA Susumu
所属
医歯薬学域 准教授
職名
准教授
外部リンク

研究キーワード

  • 異物応答

  • インビトロ評価法

  • 核内受容体

  • 異物代謝

研究分野

  • ライフサイエンス / 薬系衛生、生物化学

  • ライフサイエンス / 薬系衛生、生物化学

経歴

  • 岡山大学医歯薬学総合研究科 准教授

    2017年4月 - 現在

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所属学協会

 

論文

  • Role of YAP activation in nuclear receptor CAR-mediated proliferation of mouse hepatocytes 査読

    Taiki Abe, Yuto Amaike, Ryota Shizu, Miki Takahashi, Makoto Kano, Takuomi Hosaka, Takamitsu Sasaki, Susumu Kodama, Atsushi Matsuzawa, Kouichi Yoshinari

    Toxicological Sciences165 ( 2 ) 408 - 419   2018年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1093/toxsci/kfy149

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  • Points-to-consider documents: Scientific information on the evaluation of genetic polymorphisms during non-clinical studies and phase I clinical trials in the Japanese population. 査読 国際誌

    Masahiro Hiratsuka, Noriyasu Hirasawa, Yoshiteru Oshima, Susumu Kodama, Toshio Miyata, Takashi Dan, Hiroyuki Takatoku, Hideaki Kuribayashi, Ryosuke Nakamura, Yoshiro Saito

    Drug metabolism and pharmacokinetics33 ( 3 ) 141 - 149   2018年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Pharmacotherapy shows striking individual differences in pharmacokinetics and pharmacodynamics, involving drug efficacy and adverse reactions. Recent genetic research has revealed that genetic polymorphisms are important intrinsic factors for these inter-individual differences. This pharmacogenomic information could help develop safer and more effective precision pharmacotherapies and thus, regulatory guidance/guidelines were developed in this area, especially in the EU and US. The Project for the Promotion of Progressive Medicine, Medical Devices, and Regenerative Medicine by the Ministry of Health, Labour and Welfare, performed by Tohoku University, reported scientific information on the evaluation of genetic polymorphisms, mainly on drug metabolizing enzymes and transporters, during non-clinical studies and phase I clinical trials in Japanese subjects/patients. We anticipate that this paper will be helpful in drug development for the regulatory usage of pharmacogenomic information, most notably pharmacokinetics.

    DOI: 10.1016/j.dmpk.2018.01.005

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  • Activation of nuclear receptor CAR by an environmental pollutant perfluorooctanoic acid 査読

    Taiki Abe, Mirei Takahashi, Makoto Kano, Yuto Amaike, Chizuru Ishii, Kazuhiro Maeda, Yuki Kudoh, Toru Morishita, Takuomi Hosaka, Takamitsu Sasaki, Susumu Kodama, Atsushi Matsuzawa, Hiroyuki Kojima, Kouichi Yoshinari

    ARCHIVES OF TOXICOLOGY91 ( 6 ) 2365 - 2374   2017年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER HEIDELBERG  

    Perfluorocarboxylic acids (PFCAs) including perfluorooctanoic acid (PFOA) are environmental pollutants showing high accumulation, thermochemical stability and hepatocarcinogenicity. Peroxisome proliferator-activated receptor alpha is suggested to mediate their toxicities, but the precise mechanism remains unclear. Previous reports also imply a possible role of constitutive androstane receptor (CAR), a key transcription factor for the xenobiotic-induced expression of various genes involved in drug metabolism and disposition as well as hepatocarcinogenesis. Therefore, we have investigated whether PFCAs activate CAR. In wild-type but not Car-null mice, mRNA levels of Cyp2b10, a CAR target gene, were increased by PFOA treatment. PFCA treatment induced the nuclear translocation of CAR in mouse livers. Since CAR activators are divided into two types, ligand-type activators and phenobarbital-like indirect activators, we investigated whether PFCAs are CAR ligands or not using the cell-based reporter gene assay that can detect CAR ligands but not indirect activators. As results, neither PFCAs nor phenobarbital increased reporter activities. Interestingly, in mouse hepatocytes, pretreatment with the protein phosphatase inhibitor okadaic acid prevented an increase in Cyp2b10 mRNA levels induced by phenobarbital as reported, but not that by PFOA. Finally, in human hepatocyte-like HepaRG cells, PFOA treatment increased mRNA levels of CYP2B6, a CAR target gene, as did phenobarbital. Taken together, our present results suggest that PFCAs including PFOA are indirect activators of mouse and human CAR and that the mechanism might be different from that for phenobarbital. The results imply a role of CAR in the hepatotoxicity of PFCAs.

    DOI: 10.1007/s00204-016-1888-3

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  • Pregnenolone 16α-carbonitrile ameliorates concanavalin A-induced liver injury in mice independent of the nuclear receptor PXR activation 査読

    Susumu Kodama, Takuto Shimura, Hideaki Kuribayashi, Taiki Abe, Kouichi Yoshinari

    Toxicology Letters271   58 - 65   2017年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.toxlet.2017.02.018

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  • PXR stimulates growth factor-mediated hepatocyte proliferation by cross-talk with the FOXO transcription factor 査読

    Ryota Shizu, Taiki Abe, Satoshi Benoki, Miki Takahashi, Susumu Kodama, Masaaki Miayata, Atsushi Matsuzawa, Kouichi Yoshinari

    BIOCHEMICAL JOURNAL473 ( 3 ) 257 - 266   2016年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PORTLAND PRESS LTD  

    Growth factor-mediated hepatocyte proliferation is crucial in liver regeneration and the recovery of liver function after injury. The nuclear receptor, pregnaneXreceptor (PXR), is a key transcription factor for the xenobiotic-induced expression of genes associated with various liver functions. Recently, we reported that PXR activation stimulates xenobiotic-induced hepatocyte proliferation. In the present study, we investigated whether PXR activation also stimulates growth factor-mediated hepatocyte proliferation. In G0 phase-synchronized, immortalized mouse hepatocytes, serum or epidermal growth factor treatment increased cell growth and this growth was augmented by the expression of mouse PXR and co-treatment with pregnenolone 16 alpha-carbonitrile (PCN), a PXR ligand. In a liver regeneration model using carbon tetrachloride, PCN treatment enhanced the injury-induced increase in the number of Ki-67-positive nuclei as well as Ccna2 and Ccnb1 mRNA levels in wild-type (WT) but not Pxr-null mice. Chronological analysis of this model demonstrated that PCN treatment shifted the maximum cell proliferation to an earlier time point and increased the number of M-phase cells at those time points. In WT but not Pxr-null mice, PCN treatment reduced hepatic mRNA levels of genes involved in the suppression of G0/G1- and G1/S-phase transition, e.g. Rbl2, Cdkn1a and Cdkn1b. Analysis of the Rbl2 promoter revealed that PXR activation inhibited its Forkhead box O3 (FOXO3)-mediated transcription. Finally, the PXR-mediated enhancement of hepatocyte proliferation was inhibited by the expression of dominant active FOXO3 in vitro. The results of the present study suggest that PXR activation stimulates growth factor-mediated hepatocyte proliferation in mice, at least in part, through inhibiting FOXO3 from accelerating cell-cycle progression.

    DOI: 10.1042/BJ20150734

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  • Pregnane X Receptor Represses HNF4α Gene to Induce Insulin-Like Growth Factor-Binding Protein IGFBP1 that Alters Morphology of and Migrates HepG2 Cells 査読

    Susumu Kodama, Yuichi Yamazaki, Masahiko Negishi

    Molecular Pharmacology88 ( 4 ) 746 - 757   2015年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1124/mol.115.099341

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  • Predictive Genomic Markers for Severe Adverse Drug Reactions 招待 査読

    Yoshiro Saito, Susumu Kodama, Emiko Sugiyama, Ryosuke Nakamura

    YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN135 ( 4 ) 589 - 595   2015年4月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PHARMACEUTICAL SOC JAPAN  

    Severe adverse drug reactions are an important issue to be considered during proper drug usage in postmarketing period. Most severe adverse reactions are idiosyncratic and unrelated to their pharmacological actions via primary targets. Although these reactions were not predictable, recent developments in the field of genomics have revealed closely associated markers responsible for some severe adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). This review demonstrates genomic biomarkers for SJS/TEN and drug-induced liver injury (DILI) that were found mainly in Japanese patients and reveal ethnic differences. We and other groups have found the following associations of SJS/TEN with susceptible drugs: 1) HLA-B*58:01 for allopurinol-related cases; 2) HLA-B*15:11 and HLA-A*31:01 for carbamazepine-related cases; 3) HLA-B*51:01 for phenobarbital-related cases; 4) HLA-A*02:07 for zonisamide-related cases; 5) CYP2C9*3 for phenytoin-related cases; and 6) HLA-A*02:06 for cold medicine-related cases. The allele frequencies of these related HLA types vary among Asian populations. In addition, direct (non-covalent) binding of carbamazepine or an allopurinol metabolite, oxypurinol, to the associated HLA-type proteins was suggested. Associated genomic biomarkers are also summarized for DILI in Japanese and Caucasian populations. The application of these genomic biomarkers to prevent the onset of a reaction has been utilized in a few countries. However, in Japan, the package inserts only contain precautions that cite the research findings. To overcome this limitation, the following points should be addressed: 1) factors responsible for the development of SJS/TEN should be identified in addition to the above-mentioned HLA alleles; and 2) an inexpensive genotyping strategy and assay methods should be developed to provide a pharmacoeconomical viewpoint. Further research on severe adverse reactions is warranted.

    DOI: 10.1248/yakushi.14-00249-3

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  • Sulfotransferase genes: Regulation by nuclear receptors in response to xeno/endo-biotics 招待 査読

    Susumu Kodama, Masahiko Negishi

    DRUG METABOLISM REVIEWS45 ( 4 ) 441 - 449   2013年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:INFORMA HEALTHCARE  

    Pregnane X receptor (PXR) and constitutive active/androstane receptor (CAR), members of the nuclear receptor superfamily, are two major xeno-sensing transcription factors. They can be activated by a broad range of lipophilic xenobiotics including therapeutics drugs. In addition to xenobiotics, endogenous compounds such as steroid hormones and bile acids can also activate PXR and/or CAR. These nuclear receptors regulate genes that encode enzymes and transporters that metabolize and excrete both xenobiotics and endobiotics. Sulfotransferases (SULTs) are a group of these enzymes and sulfate xenobiotics for detoxification. In general, inactivation by sulfation constitutes the mechanism to maintain homeostasis of endobiotics. Thus, deciphering the molecular mechanism by which PXR and CAR regulate SULT genes is critical for understanding the roles of SULTs in the alterations of physiological and pathophysiological processes caused by drug treatment or environmental exposures.

    DOI: 10.3109/03602532.2013.835630

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  • PXR cross-talks with internal and external signals in physiological and pathophysiological responses 査読

    Susumu Kodama, Masahiko Negishi

    DRUG METABOLISM REVIEWS45 ( 3 ) 300 - 310   2013年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:INFORMA HEALTHCARE  

    Pregnane X receptor (PXR), an orphan member of the nuclear receptor superfamily, is a major xeno-sensing transcription factor. In response to xenobiotic exposure, PXR regulates genes involved in the metabolism and transport of xenobiotics to protect the body from their harmful effects. Recent progress has revealed that PXR responds not only to such external signals but also to internal signals to help the body adapt to changes in the internal environment, including dysregulation of the immune system. PXR responds to external and internal signals by up-or down-regulating certain metabolic pathways and cellular signals through gene regulation. PXR is a potential therapeutic target for inflammatory as well as metabolic diseases, although its activation may also have unfavorable effects on human health. This review will discuss the recent progress in the understanding of the physiological and pathophysiological roles of PXR and their implications in human diseases and drug therapy by elucidating the molecular mechanisms underlying PXR-mediated gene regulation.

    DOI: 10.3109/03602532.2013.795585

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  • Xenobiotic-induced hepatocyte proliferation associated with constitutive active/androstane receptor (CAR) or peroxisome proliferator-activated receptor α (PPARα) is enhanced by pregnane X receptor (PXR) activation in mice 査読

    Ryota Shizu, Satoshi Benoki, Yuki Numakura, Susumu Kodama, Masaaki Miyata, Yasushi Yamazoe, Kouichi Yoshinari

    PloS One8 ( 4 ) e61802   2013年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1371/journal.pone.0061802

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  • Assays of dioxins and dioxin-like compounds in actually contaminated soils using transgenic tobacco plants carrying a recombinant mouse aryl hydrocarbon receptor-mediated β-glucuronidase reporter gene expression system 査読

    Hideyuki Inui, Keiko Gion, Yasushi Utani, Taketo Wakai, Susumu Kodama, Heesoo Eun, Yun-Seok Kim, Hideo Ohkawa

    Journal of Environmental Science and Health. Part. B47 ( 1 ) 59 - 65   2012年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1080/03601234.2012.611018

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  • Assays of PCB congeners and organochlorine insecticides with the transgenic Arabidopsis and tobacco plants carrying recombinant guinea pig AhR and GUS reporter genes 査読

    Keiko Gion, Hideyuki Inui, Hideaki Sasaki, Yasushi Utani, Susumu Kodama, Hideo Ohkawa

    JOURNAL OF ENVIRONMENTAL SCIENCE AND HEALTH PART B-PESTICIDES FOOD CONTAMINANTS AND AGRICULTURAL WASTES47 ( 7 ) 599 - 607   2012年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:TAYLOR & FRANCIS INC  

    Certain congeners of polychlorinated biphenyls (PCBs) and organochlorine insecticides are ligands of aryl hydrocarbon receptors (AhRs) in animals. A recombinant guinea pig (g) AhR, XgDV, was constructed by fusing the ligand-binding domain of gAhR, the DNA-binding domain of LexA, and the transactivating domain of VP16. Then, the expression unit of beta-glucuronidase (GUS) reporter gene regulated by XgDV was introduced into Arabidopsis and tobacco plants. When the transgenic Arabidopsis XgDV plants were cultured on Murashige-Skoog (MS) medium containing PCB congeners, the GUS activity in the plants increased toxic equivalent (TEQ)-dependently. The GUS activity in the transgenic Arabidopsis XgDV plants cultured on MS medium containing the organochlorine insecticide dieldrin was also induced. On the other hand, in the case of DDT, the GUS activity induced by 3-methylcholanthere in the plants decreased. The transgenic Arabidopsis XgDV plants detected 1000 ng g(-1) PCB126 in 1 g of soils. Thus the XgDV plants seemed to be useful for convenient assays of PCB congeners and organochlorine insecticides, without any extraction and purification steps.

    DOI: 10.1080/03601234.2012.668453

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  • Liganded pregnane X receptor represses the human sulfotransferase SULT1E1 promoter through disrupting its chromatin structure 査読

    Susumu Kodama, Fardin Hosseinpour, Joyce A. Goldstein, Masahiko Negishi

    NUCLEIC ACIDS RESEARCH39 ( 19 ) 8392 - 8403   2011年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    Pregnane X receptor (PXR), acting as a xenobiotic-activated transcription factor, regulates the hepatic metabolism of therapeutics as well as endobiotics such as steroid hormones. Given our finding that PXR activation by rifampicin (RIF) represses the estrogen sulfotransferase (SULT1E1) gene in human primary hepatocytes and hepatocellular carcinoma Huh7 cells, here we have investigated the molecular mechanism of this repression. First the PXR-responsive enhancer was delineated to a 100 bp sequence (-1000/-901), which contains three half sites that constitute the overlapping direct repeat 1 (DR1) and direct repeat 2 (DR2) motifs and two forkhead factor binding sites. siRNA knockdown, chromatin immunoprecipitation and chromatin conformation capture assays were employed to demonstrate that hepatocyte nuclear factor 4 alpha (HNF4 alpha) bound to the PXR-responsive enhancer, and activated the enhancer by looping its position close to the proximal promoter. Upon activation by RIF, PXR indirectly interacted with the enhancer, decreasing the interaction with HNF4 alpha and dissolving the looped SULT1E1 promoter with deacetylation of histone 3. Removal of the DR sites from the enhancer hampers the ability of HNF4 alpha to loop the promoter and that of PXR to repress the promoter activity. Thus, PXR represses human SULT1E1, possibly attenuating the inactivation of estrogen.

    DOI: 10.1093/nar/gkr458

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  • Pregnane X Receptor PXR Activates the GADD45 beta Gene, Eliciting the p38 MAPK Signal and Cell Migration 査読

    Susumu Kodama, Masahiko Negishi

    JOURNAL OF BIOLOGICAL CHEMISTRY286 ( 5 ) 3570 - 3578   2011年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

    Pregnane X receptor (PXR) was originally characterized as a transcription factor that induces hepatic drug metabolism by activating cytochrome P450 genes. Here we have now demonstrated a novel function of PXR, that of eliciting p38 mitogen-activated protein kinase (MAPK) phosphorylation for cell migration. Upon xenobiotic activation of ectopic human PXR, human hepatocellular carcinoma HepG2 cells were found to exhibit increased phosphorylation of p38 MAPK and to subsequently change morphology and migrate. p38 MAPK was responsible for the regulation of these morphological changes and cell migration because the p38 MAPK inhibitor SB239063 repressed both. Prior to this phosphorylation, PXR directly activated the early response GADD45 beta gene by binding to a distal direct repeat 4 site of the GADD45 beta promoter. Ectopic expression of GADD45 beta increased p38 MAPK phosphorylation, whereas siRNA knockdown of GADD45 beta decreased the PXR-induced p38 MAPK phosphorylation, confirming that GADD45 beta can regulate PXR-induced p38 MAPK phosphorylation in HepG2 cells. These results indicate that PXR activates the GADD45 beta gene, increasing p38 MAPK phosphorylation, and leading HepG2 cells to change morphology and migrate. The GADD45 beta gene is a direct target for PXR, eliciting cell signals to regulate various cellular functions.

    DOI: 10.1074/jbc.M110.179812

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  • Nuclear Xenobiotic Receptor Pregnane X Receptor Locks Corepressor Silencing Mediator for Retinoid and Thyroid Hormone Receptors (SMRT) onto the CYP24A1 Promoter to Attenuate Vitamin D-3 Activation 査読

    Yoshihiro Konno, Susumu Kodama, Rick Moore, Nobuhiro Kamiya, Masahiko Negishi

    MOLECULAR PHARMACOLOGY75 ( 2 ) 265 - 271   2009年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS  

    We have studied the molecular mechanism by which the nuclear xenobiotic receptors pregnane X receptor (PXR) and constitutive active/androstane receptor (CAR) regulate transcription of the vitamin D-3 24-hydroxylase (CYP24A1) gene. In the absence of vitamin D-3, PXR activates the CYP24A1 gene by directly binding to and transactivating vitamin D-response elements (VDREs) within its promoter. Vitamin D-3 activates the CYP24A1 promoter by dissociating the corepressor silencing mediator for retinoid and thyroid hormone receptors ( SMRT) from the vitamin D receptor (VDR) on those VDREs. PXR strongly represses vitamin D-3 activation of the CYP24A1 gene, in which PXR indirectly binds to and prevents vitamin D-3-dependent dissociation of SMRT from the CYP24A1 promoter. The degree of the PXR-mediated locking of SMRT depends on the relative concentration of vitamin D 3 to the human PXR activator rifampicin; SMRT increased its dissociation as this ratio increased. CAR is also found to prevent dissociation of SMRT from the CYP24A1 promoter. Thus, our present study defines the novel molecular mechanism by which PXR and CAR mediate drug interactions with vitamin D 3 to regulate the CYP24A1 gene. Pxr(+/+) and Pxr(-/-) mice were continuously treated with mouse PXR activator PCN to evaluate the hypothesis that induction of the Cyp24a1 gene is responsible for the loss of bone mineral density often observed in patients treated continuously with PXR-activating drugs. PCN-dependent loss of mineral density is observed in the metaphyseal bones of only the Pxr(+/+) mice. This loss, however, does not correlate with the expression levels of the Cyp24a1 gene in these mice.

    DOI: 10.1124/mol.108.051904

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  • Recombinant aryl hydrocarbon receptors for bioassay of aryl hydrocarbon receptor ligands in transgenic tobacco plants 査読

    Susumu Kodama, Kumiko Okada, Keiko Akimoto, Hideyuki Inui, Hideo Ohkawa

    PLANT BIOTECHNOLOGY JOURNAL7 ( 2 ) 119 - 128   2009年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL PUBLISHING, INC  

    Dioxin residues widely contaminate soil and agricultural products at low concentrations and may accumulate in organisms at the top of food chains owing to their physicochemical properties. In this study, we have developed novel, dioxin-inducible, reporter gene expression systems regulated by recombinant aryl hydrocarbon receptors (AhRs). The recombinant AhRs, referred to as XDVs, consist of the DNA-binding domain of the bacterial repressor protein LexA, a 90-kDa heat shock protein- and ligand-binding regulatory domain from mouse AhR, and the transactivation domain of herpes simplex virus regulatory protein VP16. Transgenic tobacco plants carrying XDVs absorb various AhR ligands, including 3-methylcholanthrene, beta-naphthoflavone and indigo from solid medium and vermiculite, and show dose- and time-dependent expression of the beta-glucuronidase reporter gene. The results clearly suggest that XDVs are functional transcription factors that respond to AhR ligands, and that the XDV-mediated reporter gene expression system is applicable to bioassays for dioxin residues in the environment.

    DOI: 10.1111/j.1467-7652.2008.00378.x

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  • The roles of nuclear receptors CAR and PXR in hepatic energy metabolism 招待 査読

    Yoshihiro Konno, Masahiko Negishi, Susumu Kodama

    DRUG METABOLISM AND PHARMACOKINETICS23 ( 1 ) 8 - 13   2008年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JAP SOC STUDY XENOBIOTICS  

    Nuclear receptors constitutive active/androstane receptor (CAR) and pregnane X receptor (PXR) were originally characterized as transcription factors regulating the hepatic genes that encode drug metabolizing enzymes. Recent works have now revealed that these nuclear receptors also play the critical roles in modulating hepatic energy metabolism. While CAR and PXR directly bind to their response sequences phenobarbital-responsive enhancer module (PBREM) and xenobiotic responsive enhancer module (XREM) in the promoter of target genes to increase drug metabolism, the receptors also cross talk with various hormone responsive transcription factors such as forkhead box O1 (FoxO1), forkhead box A2 (FoxA2), cAMP-response element binding protein, and peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC 1 alpha) to decrease energy metabolism through down-regulating gluconeogenesis, fatty acid oxidation and ketogenesis and up-regulating lipogenesis. In addition, CAR modulates thyroid hormone activity by regulating type 1 deiodinase in the regenerating liver. Thus, CAR and PXR are now placed at the crossroad where both xenobiotics and endogenous stimuli co-regulate liver function.

    DOI: 10.2133/dmpk.23.8

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  • Aryl hydrocarbon receptor (AhR)-mediated reporter gene expression systems in transgenic tobacco plants 査読

    Stisumu Kodama, Kumiko Okada, Hideyuki Inui, Hideo Ohkawa

    PLANTA227 ( 1 ) 37 - 45   2007年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    In mammals, the aryl hydrocarbon receptor (AhR) mediates expression of certain genes, including CYP1A1, in response to exposure to dioxins and related compounds. We have constructed a mouse AhR-mediated gene expression systems for a beta-glucuronidase (GUS) reporter gene consisting of an AhR, an AhR nuclear translocator (Arnt), and a xenobiotic response element (XRE)-driven promoter in transgenic tobacco plants. On treatment with the AhR ligands 3-methyl-cholanthrene (MC), beta-naphthoflavone (beta NF), and indigo, the transgenic tobacco plants exhibited enhanced GUS activity, presumably by inducible expression of the reporter gene. The recombinant AhR (AhRV), with the activation domain replaced by that of the Herpes simplex virus protein VP16, induced GUS activity much more than the wild-type AhR in the transgenic tobacco plants. Plants carrying AhRV expressed the GUS reporter gene in a dose- and time-dependent manner when treated with MC; GUS activity was detected at 5 nM MC on solid medium and at 12 h after soaking in 25 mu M MC. Histochemical GUS staining showed that this system was active mainly in leaf and stem. These results suggest that the AhR-mediated reporter gene expression system has potential for the bioassay of dioxins in the environment and as a novel gene expression system in plants.

    DOI: 10.1007/s00425-007-0592-1

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  • Human nuclear pregnane X receptor cross-talk with CREB to repress cAMP activation of the glucose-6-phosphatase gene 査読

    Susumu Kodama, Rick Moore, Yukio Yamamoto, Masahiko Negishi

    BIOCHEMICAL JOURNAL407 ( Pt 3 ) 373 - 381   2007年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PORTLAND PRESS LTD  

    The nuclear PXR (pregnane X receptor) was originally characterized as a key transcription factor that activated hepatic genes encoding drug-metabolizing enzymes. We have now demonstrated that PXR also represses glucagon-activated transcription of the G6Pase (glucose-6-phosphatase) gene by directly binding to CREB [CRE (CAMP-response element)-binding protein]. Adenoviral-mediated expression of human PXR (hPXR) and its activation by rifampicin strongly repressed cAMP-dependent induction of the endogenous G6Pase gene in Huh7 cells. Using the - 259 by G6Pase promoter construct in cell-based transcription assays, repression by hPXR of PKA (CAMP-dependent protein kinase)-mediated promoter activation was delineated to CRE sites. GST (glutathione transferase) pull-down and immunoprecipitation assays were employed to show that PXR binds directly to CREB, while gel-shift assays were used to demonstrate that this binding prevents CREB interaction with the CRE. These results are consistent with the hypothesis that PXR represses the transcription of the G6Pase gene by inhibiting the DNA-binding ability of CREB. In support of this hypothesis, treatment with the mouse PXR activator PCN (pregnenolone 16 alpha-carbonitrile) repressed CAMP-dependent induction of the G6Pase gene in primary hepatocytes prepared from wild-type, but not from PXR-knockout, mice, and also in the liver of fasting wildtype, but not PXR-knockout, mice. Moreover, ChIP (chromatin immunoprecipitation) assays were performed to show a decreased CREB binding to the G6Pase promoter in fasting wild-type mice after PCN treatment. Thus drug activation of PXR can repress the transcriptional activity of CREB, down-regulating gluconeogenesis.

    DOI: 10.1042/BJ20070481

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  • Phenobarbital confers its diverse effects by activating the orphan nuclear receptor car 招待 査読

    S Kodama, M Negishi

    DRUG METABOLISM REVIEWS38 ( 1-2 ) 75 - 87   2006年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:TAYLOR & FRANCIS INC  

    In the early 1960s, phenobarbital (PB) was shown to induce hepatic drug metabolism and the induction was implicated in the molecular mechanism of drug tolerance development. Since then, it has become evident that PB not only induces drug metabolism, but also triggers pleiotropic effects on liver function., such as cell growth and communication, proliferation of the endoplasmic reticulum, tumor promotion, glucose metabolism, steroid/thyroid hormone metabolism, and bile acid synthesis. Upon activation by PB and numerous PB-type inducers, the nuclear receptor CAR mediates those pleiotropic actions by regulating various hepatic genes, utilizing multiple regulatory mechanisms.

    DOI: 10.1080/03602530600569851

    Web of Science

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  • Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate genes that encode drug-metabolizing and gluconeogenic enzymes 査読

    S Kodama, C Koike, M Negishi, Y Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY24 ( 18 ) 7931 - 7940   2004年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC MICROBIOLOGY  

    The nuclear receptors CAR and PXR activate hepatic genes in response to therapeutic drugs and xenobiotics, leading to the induction of drug-metabolizing enzymes, such as cytochrome P450. Insulin inhibits the ability of FOXO1 to express genes encoding gluconeogenic enzymes. Induction by drugs is known to be decreased by insulin, whereas gluconeogenic activity is often repressed by treatment with certain drugs, such as phenobarbital (PB). Performing cell-based transfection assays with drug-responsive and insulin-responsive enhancers, glutathione S-transferase pull down, RNA interference (RNAi), and mouse primary hepatocytes, we examined the molecular mechanism by which nuclear receptors and FOXO1 could coordinately regulate both enzyme pathways. FOXO1 was found to be a coactivator to CAR- and PXR-mediated transcription. In contrast, CAR and PXR, acting as corepressors, downregulated FOXO1-mediated transcription in the presence of their activators, such as 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) and pregnenolone 16alpha-carbonitrile, respectively. A constitutively active mutant of the insulin-responsive protein kinase Akt, but not the kinase-negative mutant, effectively blocked FOXO1 activity in cell-based assays. Thus, insulin could repress the receptors by activating the Akt-FOXO1 signal, whereas drugs could interfere with FOXO1-mediated transcription by activating CAR and/or PXR. Treatment with TCPOBOP or PB decreased the levels of phosphoenolpyruvate carboxykinase 1 mRNA in mice but not in Car(-/-) mice. We conclude that FOXO1 and the nuclear receptors reciprocally coregulate their target genes, modulating both drug metabolism and gluconeogenesis.

    DOI: 10.1128/MCB.24.18.7931.7940.2004

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  • Expression of human cytochromes P450 1A1 and P450 1A2 as fused enzymes with yeast NADPH-cytochrome P450 oxidoreductase in transgenic tobacco plants 査読

    N Shiota, S Kodama, H Inui, H Ohkawa

    BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY64 ( 10 ) 2025 - 2033   2000年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:TAYLOR & FRANCIS LTD  

    Among 11 isoforms of the human cytochrome P450 enzymes metabolizing xenobiotics, CYP 1A1 and CYP 1A2 were major P450 species in the metabolism of the herbicides chlortoluron and atrazine in a yeast expression system. CYP1A2 was more active in the metabolism of both herbicides than CYP1A1, The fused enzymes of CYP1A1 and CYP1A2 with yeast NADPH-cytochrome P450 oxidoreductase were functionally active in the microsomal fraction of the yeast Saccharomyces cerevisiae and showed increased specific activity towards 7-ethoxyresorufin as compared to CYP1A1 and CYP1A2 alone. Then, both fused enzymes were each expressed in the microsomes of tobacco (Nicotiana tabacum cv, Samsun NN) plants. The transgenic plants expressing the CYP1A2 fusion enzyme had higher resistance to the herbicide chlortoluron than the plants expressing the CYP1A1 fusion enzyme did, The transgenic plants expressing the CYP1A2 fused enzyme metabolized chlortoluron to a larger extent to its non-phytotoxic metabolites through N-demethylation and ring-methyl hydroxylation as compared to the plants expressing the CYP1A1 fused enzyme. Thus, the possibility of increasing the herbicide resistance in the transgenic plants by the selection of P450 species and the fusion with P450 reductase is discussed.

    DOI: 10.1271/bbb.64.2025

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共同研究・競争的資金等の研究

  • 生体要因による薬物動態の変動:サイトカインシグナルを介した調節メカニズムの解明

    2016年04月 - 2019年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C) 

    児玉 進

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    担当区分:研究代表者  資金種別:競争的資金

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  • 薬物性筋障害発症へのHLAクラスII分子関与に基づく新たな解析戦略・評価系の構築

    2015年04月 - 2018年03月

    日本学術振興会  科学研究費助成事業 挑戦的萌芽研究 

    斎藤 嘉朗

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    資金種別:競争的資金

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  • 免疫応答のバランスを調節する核内受容体PXRの新規な生理機能の解明

    2014年04月 - 2017年03月

    日本学術振興会  科学研究費助成事業 若手研究(B) 

    児玉 進

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    担当区分:研究代表者  資金種別:競争的資金

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  • 核内受容体PXRの新規生理機能:免疫メンテナンスの解明

    2012年04月 - 2014年03月

    日本学術振興会  科学研究費助成事業 若手研究(B) 

    児玉 進

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    担当区分:研究代表者  資金種別:競争的資金

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  • 化学物質のヒトでの安全性評価のための核内受容体CARを介した肝発がん機構の解明

    2012年04月 - 2013年03月

    日本学術振興会  科学研究費助成事業 挑戦的萌芽研究 

    山添 康

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    資金種別:競争的資金

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