Updated on 2025/10/23

写真a

 
KODAMA Susumu
 
Organization
Faculty of Medicine, Dentistry and Pharmaceutical Sciences Associate Professor
Position
Associate Professor
External link

Degree

  • 博士（農学） ( 2003.3   神戸大学 )

  • agriculture ( 2003.3   Kobe University )

  • 修士（農学） ( 2000.3   神戸大学 )

  • 学士（農学） ( 1998.3   神戸大学 )

Research Interests

  • Xenobiotic response

  • in vitro assay

  • nuclear receptor

  • xenobiotic metabolism

Research Areas

  • Life Science / Pharmaceutical hygiene and biochemistry

Research History

  • 岡山大学医歯薬学総合研究科 准教授

    2017.4

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Professional Memberships

  • THE JAPANESE SOCIETY OF TOXICOLOGY

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  • THE JAPANESE SOCIETY FOR THE STUDY OF XENOBIOTICS

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  • THE PHARMACEUTICAL SOCIETY OF JAPAN

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Papers

  • Structural characterization of 1,3-bis-tert-butyl monocyclic benzene derivatives with agonistic activity towards retinoid X receptor alpha Reviewed International journal

    Susumu Kodama, Shuzo Matsumoto, Yuta Takamura, Michiko Fujihara, Masaki Watanabe, Atsushi Ono, Hiroki Kakuta

    Toxicology Letters   373   76 - 83   2022.11

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    Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

    Retinoid X receptor alpha (RXRα) plays pivotal roles in multiple biological processes, but limited information is available on the structural features of chemicals that show low affinity for RXRα, but nevertheless cause significant activation, though these may represent a human health hazard. We recently discovered that several industrial chemicals having 1,3-bis-tert-butylbenzene as a common chemical structure exhibit agonistic activity towards rat RXRα. In this study, we explored the structure-activity relationship of 1,3-bis-tert-butyl monocyclic benzene derivatives for RXRα activation by means of in vitro and in silico analyses. The results indicate that a bulky substituent at the 5-position is favorable for agonistic activity towards human RXRα. Since 1,3-bis-tert-butyl monocyclic benzene derivatives with bulky hydrophobic moieties differ structurally from known RXRα ligands such as 9-cis-retinoic acid and bexarotene, our findings may be helpful for the development of structural alerts in the safety evaluation of industrial chemicals for RXRα-based toxicity to living organisms.

    DOI： 10.1016/j.toxlet.2022.11.003

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  • Association between in vitro nuclear receptor-activating profiles of chemical compounds and their in vivo hepatotoxicity in rats Reviewed

    Susumu Kodama, Nao Yoshii, Akihiro Ota, Jun-ichi Takeshita, Kouichi Yoshinari, Atsushi Ono

    The Journal of Toxicological Sciences   46 ( 12 )   569 - 587   2021.12

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    Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Toxicology  

    The liver plays critical roles to maintain homeostasis of living organisms and is also a major target organ of chemical toxicity. Meanwhile, nuclear receptors (NRs) are known to regulate major liver functions and also as a critical target for hepatotoxic compounds. In this study, we established mammalian one-hybrid assay systems for five rat-derived NRs, namely PXR, PPARα, LXRα, FXR and RXRα, and evaluated a total of 326 compounds for their NR-activating profiles. Then, we assessed the association between their NR-activating profile and hepatotoxic endpoints in repeated-dose toxicity data of male rats from Hazard Evaluation Support System. In the in vitro cell-based assays, 68, 38, 20, 17 and 17 compounds were identified as positives for PXR, PPARα, LXRα, FXR and RXRα, respectively. The association analyses demonstrated that the PXR-positive compounds showed high frequency of endpoints related to liver hypertrophy, such as centrilobular hepatocellular hypertrophy, suggesting that PXR activation is involved in chemical-induced liver hypertrophy in rats. It is intriguing to note that the PXR-positive compounds also showed statistically significant associations with both prolonged activated partial thromboplastin time and prolonged prothrombin time, suggesting a possible involvement of PXR in the regulation of blood clotting factors. Collectively, our approach may be useful for discovering new functions of NRs as well as understanding the complex mechanism for hepatotoxicity caused by chemical compounds.

    DOI： 10.2131/jts.46.569

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  • PXR Functionally Interacts with NF-κB and AP-1 to Downregulate the Inflammation-Induced Expression of Chemokine CXCL2 in Mice. Reviewed International journal

    Maya Okamura, Ryota Shizu, Taiki Abe, Susumu Kodama, Takuomi Hosaka, Takamitsu Sasaki, Kouichi Yoshinari

    Cells   9 ( 10 )   2020.10

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    Language：English   Publishing type：Research paper (scientific journal)  

    Pregnane X receptor (PXR) is a liver-enriched xenobiotic-responsive transcription factor. Although recent studies suggest that PXR shows anti-inflammatory effects by suppressing nuclear factor kappa B (NF-κB), the detailed mechanism remains unclear. In this study, we aimed to elucidate this mechanism. Mice were treated intraperitoneally with the PXR agonist pregnenolone 16α-carbonitrile (PCN) and/or carbon tetrachloride (CCl4). Liver injury was evaluated, and hepatic mRNA levels were determined via quantitative reverse transcription polymerase chain reaction. Reporter assays with wild-type and mutated mouse Cxcl2 promoter-containing reporter plasmids were conducted in 293T cells. Results showed that the hepatic expression of inflammation-related genes was upregulated in CCl4-treated mice, and PCN treatment repressed the induced expression of chemokine-encoding Ccl2 and Cxcl2 among the genes investigated. Consistently, PCN treatment suppressed the increased plasma transaminase activity and neutrophil infiltration in the liver. In reporter assays, tumor necrosis factor-α-induced Cxcl2 expression was suppressed by PXR. Although an NF-κB inhibitor or the mutation of an NF-κB-binding motif partly reduced PXR-dependent suppression, the mutation of both NF-κB and activator protein 1 (AP-1) sites abolished it. Consistently, AP-1-dependent gene transcription was suppressed by PXR with a construct containing AP-1 binding motifs. In conclusion, the present results suggest that PXR exerts anti-inflammatory effects by suppressing both NF-κB- and AP-1-dependent chemokine expression in mouse liver.

    DOI： 10.3390/cells9102296

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  • Functional interaction between PXR and YAP in xenobiotic-dependent liver hypertrophy and drug metabolism. Reviewed

    Abe T, Shizu R, Sasaki T, Shimizu Y, Hosaka T, Kodama S, Matsuzawa A, Yoshinari K

    The Journal of pharmacology and experimental therapeutics   371 ( 3 )   590 - 601   2019.9

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1124/jpet.119.258632

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  • Role of YAP activation in nuclear receptor CAR-mediated proliferation of mouse hepatocytes Reviewed International journal

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

    Toxicological Sciences   165 ( 2 )   408 - 419   2018.10

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    Language：English   Publishing type：Research paper (scientific journal)  

    Constitutive androstane receptor (CAR) is a xenobiotic-responsive nuclear receptor that is highly expressed in the liver. CAR activation induces hepatocyte proliferation and hepatocarcinogenesis in rodents, but the mechanisms remain unclear. In this study, we investigated the association of CAR-dependent cell proliferation with Yes-associated protein (YAP), which is a transcriptional cofactor controlling organ size and cell growth through the interaction with various transcriptional factors including TEA domain family member (TEAD). In mouse livers, 1,4-bis-(2-[3,5-dichloropyridyloxy])benzene (TCPOBOP) (a mouse CAR [mCAR] activator) treatment increased the nuclear YAP accumulation and mRNA levels of YAP target genes as well as cell-cycle related genes along with liver hypertrophy and verteporfin (an inhibitor of YAP/TEAD interaction) cotreatment tended to attenuate them. Furthermore, in cell-based reporter gene assays, CAR activation enhanced the YAP/TEAD-dependent transcription. To investigate the role of YAP/TEAD activation in the CAR-dependent hepatocyte proliferation, we sought to establish an in vitro system completely reproducing CAR-dependent cell proliferation. Since CAR was only slightly expressed in cultured mouse primary hepatocytes compared with mouse livers and no proliferation was observed after treatment with TCPOBOP, we overexpressed CAR using mCAR expressing adenovirus (Ad-mCAR-V5) in mouse primary hepatocytes. Ad-mCAR-V5 infection and TCPOBOP treatment induced hepatocyte proliferation. Similar results were obtained with immortalized normal mouse hepatocytes as well. In the established in vitro system, CAR-dependent proliferation was strongly inhibited by Yap knockdown and completely abolished by verteporfin treatment. Our present results obtained in in vivo and in vitro experiments suggest that YAP/TEAD activation plays key roles in CAR-dependent proliferation of murine hepatocytes.

    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. Reviewed International journal

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

    Drug metabolism and pharmacokinetics   33 ( 3 )   141 - 149   2018.6

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    Language：English   Publishing type：Research paper (scientific journal)  

    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 Reviewed

    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 TOXICOLOGY   91 ( 6 )   2365 - 2374   2017.6

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1007/s00204-016-1888-3

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

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

    TOXICOLOGY LETTERS   271   58 - 65   2017.4

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    Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

    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 Reviewed

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

    BIOCHEMICAL JOURNAL   473 ( 3 )   257 - 266   2016.2

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1042/BJ20150734

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  • Pregnane X Receptor Represses HNF4 alpha Gene to Induce Insulin-Like Growth Factor-Binding Protein IGFBP1 that Alters Morphology of and Migrates HepG2 Cells Reviewed

    Susumu Kodama, Yuichi Yamazaki, Masahiko Negishi

    MOLECULAR PHARMACOLOGY   88 ( 4 )   746 - 757   2015.10

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1124/mol.115.099341

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  • Predictive Genomic Markers for Severe Adverse Drug Reactions Invited Reviewed

    Yoshiro Saito, Susumu Kodama, Emiko Sugiyama, Ryosuke Nakamura

    YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN   135 ( 4 )   589 - 595   2015.4

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    Language：Japanese   Publishing type：Research paper (scientific journal)  

    DOI： 10.1248/yakushi.14-00249-3

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  • 特異体質性薬物毒性の研究最前線 重篤副作用に関する予測ゲノムマーカー

    斎藤 嘉朗, 児玉 進, 杉山 永見子, 中村 亮介

    薬学雑誌   135 ( 4 )   589 - 595   2015.4

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

    Susumu Kodama, Masahiko Negishi

    DRUG METABOLISM REVIEWS   45 ( 4 )   441 - 449   2013.11

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    Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.3109/03602532.2013.835630

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

    Susumu Kodama, Masahiko Negishi

    DRUG METABOLISM REVIEWS   45 ( 3 )   300 - 310   2013.8

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    Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

    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 alpha (PPAR alpha) Is Enhanced by Pregnane X Receptor (PXR) Activation in Mice Reviewed

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

    PLOS ONE   8 ( 4 )   e61802   2013.4

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1371/journal.pone.0061802

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  • 医療品評価をめぐる最近の話題 市販後安全性確保に係るバイオマーカーと診断

    斎藤 嘉朗, 前川 京子, 田島 陽子, 児玉 進, 黒瀬 光一

    レギュラトリーサイエンス学会誌   3 ( 1 )   43 - 55   2013.1

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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 .BETA.-glucuronidase reporter gene expression system Reviewed

    INUI Hideyuki, GION Keiko, UTANI Yasushi, WAKAI Taketo, KODAMA Susumu, KODAMA Susumu, EUN Heesoo, KIM Yun-Seok

    Journal of Environmental Science and Health. Part B. Pesticides, Food Contaminants, and Agricultural Wastes   47 ( 4 )   233 - 239   2012.4

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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 beta-glucuronidase reporter gene expression system (Retracted article. See vol. 47, pg. 759, 2012) Reviewed

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

    JOURNAL OF ENVIRONMENTAL SCIENCE AND HEALTH PART B-PESTICIDES FOOD CONTAMINANTS AND AGRICULTURAL WASTES   47 ( 1 )   59 - 65   2012

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    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 Reviewed

    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 WASTES   47 ( 7 )   599 - 607   2012

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    Language：English   Publishing type：Research paper (scientific journal)  

    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 Reviewed

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

    NUCLEIC ACIDS RESEARCH   39 ( 19 )   8392 - 8403   2011.10

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    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 Reviewed

    Susumu Kodama, Masahiko Negishi

    JOURNAL OF BIOLOGICAL CHEMISTRY   286 ( 5 )   3570 - 3578   2011.2

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    Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

    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 Reviewed

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

    MOLECULAR PHARMACOLOGY   75 ( 2 )   265 - 271   2009.2

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    Language：English   Publishing type：Research paper (scientific journal)  

    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 Reviewed

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

    PLANT BIOTECHNOLOGY JOURNAL   7 ( 2 )   119 - 128   2009.2

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    Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

    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 Invited Reviewed

    Yoshihiro Konno, Masahiko Negishi, Susumu Kodama

    DRUG METABOLISM AND PHARMACOKINETICS   23 ( 1 )   8 - 13   2008

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.2133/dmpk.23.8

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

    Stisumu Kodama, Kumiko Okada, Hideyuki Inui, Hideo Ohkawa

    PLANTA   227 ( 1 )   37 - 45   2007.12

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    Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

    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 Reviewed

    Susumu Kodama, Rick Moore, Yukio Yamamoto, Masahiko Negishi

    BIOCHEMICAL JOURNAL   407 ( Pt 3 )   373 - 381   2007.11

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    Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1042/BJ20070481

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  • Phenobarbital confers its diverse effects by activating the orphan nuclear receptor car Invited Reviewed

    S Kodama, M Negishi

    DRUG METABOLISM REVIEWS   38 ( 1-2 )   75 - 87   2006

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    Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1080/03602530600569851

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  • Monitoring of endocrine disruptors in transgenic plants carrying aryl hydrocarbon receptor and estrogen receptor genes Reviewed

    H Inui, H Sasaki, S Kodama, NH Chua, H Ohkawa

    NEW DISCOVERIES IN AGROCHEMICALS   892   40 - 47   2005

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

    S Kodama, C Koike, M Negishi, Y Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY   24 ( 18 )   7931 - 7940   2004.9

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    Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

    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 Reviewed

    N Shiota, S Kodama, H Inui, H Ohkawa

    BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY   64 ( 10 )   2025 - 2033   2000.10

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1271/bbb.64.2025

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MISC

  • IL-6刺激に応答した薬物代謝酵素CYP1A2遺伝子の転写抑制メカニズムの解明 Reviewed

    柳田 翔太, 吉井 奈穂, 森 彩美, 小野 敦, 児玉 進

    日本薬学会年会要旨集 134年会   2020.3

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  • 核内受容体PXRのフェノール系酸化防止剤に対する応答性のヒト－ラット間における種差

    勝目誠, 神高明宏, 小野敦, 児玉進

    第51回日本毒性学会年会要旨集   2024.7

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  • 核内受容体PXRのフェノール系酸化防止剤に対する応答性のヒト－ラット間における種差

    勝目 誠, 神高明宏, 小野 敦, 児玉 進

    おかやまバイオアクティブ研究会 第63回シンポジウム 発表要旨集   2023.9

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  • 化学物質のin vitro核内受容体活性化プロファイルとin vivoラット肝毒性フェノタイプとの関連性の評価 Reviewed

    児玉 進, 吉井 奈穂, 大田 明弘, 吉成 浩一, 小野 敦

    第48回 日本毒性学会 要旨集   2021.7

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  • 化学物質の核内受容体プロファイルとラット反復投与毒性試験における毒性フェノタイプの関連解析

    吉井 奈穂, 児玉 進, 大田 明弘, 吉成 浩一, 小野 敦

    第6回 次世代を担う若手のためのレギュラトリーサイエンスフォーラム 要旨集   2020.11

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  • 薬物性肝障害におけるエクソソームの働き：肝細胞から免疫系への情報伝達 Invited Reviewed

    児玉 進

    ファルマシア   56 ( 1 )   70   2020.1

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    Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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  • Scientific Information on the Evaluation of Genetic Polymorphisms During Non-clinical Studies and PhaseI Clinical Trials in the Japanese Population

    平塚真弘, 平塚真弘, 平塚真弘, 平澤典保, 平澤典保, 大島吉輝, 大島吉輝, 児玉進, 児玉進, 児玉進, 宮田敏男, 段孝, 高徳敬之, 栗林秀明, 中村亮介, 中村亮介, 斎藤嘉朗, 斎藤嘉朗

    レギュラトリーサイエンス学会誌   9 ( 2 )   95‐102(J‐STAGE) - 102   2019

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  • PXR STIMULATES THE GROWTH FACTOR-MEDIATED HEPATOCYTE PROLIFERATION BY INHIBITING FOXO-MEDIATED TRANSCRIPTION OF CELL CYCLE SUPPRESSOR GENES Reviewed

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

    DRUG METABOLISM AND PHARMACOKINETICS   32 ( 1 )   S24 - S24   2017.1

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    Language：English   Publishing type：Research paper, summary (international conference)  

    DOI： 10.1016/j.dmpk.2016.10.119

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  • 核内受容体PXRの抗炎症作用におけるNF-κBの寄与の解析

    岡村麻絢, 阿部太紀, 鶴田聡志, 志津怜太, 保坂卓臣, 佐々木崇光, 児玉進, 吉成浩一

    衛生薬学・環境トキシコロジー講演要旨集   2017   2017

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  • 核内受容体PXRと臓器サイズ制御シグナルHippo pathwayのクロストーク Reviewed

    阿部 太紀, 保坂 卓臣, 佐々木 崇光, 児玉 進, 松沢 厚, 吉成 浩一

    The Journal of Toxicological Sciences   41 ( Suppl. )   S250 - S250   2016.6

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    Language：Japanese   Publisher：(一社)日本毒性学会  

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  • 核内受容体PXR活性化による四塩化炭素誘発性肝障害の軽減作用 Reviewed

    倉冨 雅, 阿部 太紀, 児玉 進, 吉成 浩一

    The Journal of Toxicological Sciences   40 ( Suppl. )   S205 - S205   2015.6

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  • 次世代シーケンサーを用いた広領域多型解析に向けた解析試料の品質要件

    児玉 進, 平塚 真弘, 中村 亮介, 平澤 典保, 斎藤 嘉朗

    日本薬学会年会要旨集   135年会 ( 3 )   178 - 178   2015.3

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  • 臨床における重症薬疹とゲノムマーカー (皮膚毒性)

    岡本(内田) 好海, 児玉 進, 中村 亮介, 斎藤 嘉朗

    谷本学校毒性質問箱   ( 17 )   18 - 23   2015

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  • 特異体質性薬物毒性の研究最前線 重篤副作用に関する予測ゲノムマーカー

    斎藤 嘉朗, 児玉 進, 杉山 永見子, 中村 亮介

    日本薬学会年会要旨集   134年会 ( 1 )   207 - 207   2014.3

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  • UNIQUE ROLE OF PXR IN THE HEPATOCYTE PROLIFERATION IN MICE Reviewed

    Ryota Shizu, Satoshi Benoki, Miki Takahashi, Susumu Kodama, Yasushi Yamazoe, Kouichi Yoshinari

    DRUG METABOLISM REVIEWS   45   231 - 232   2014.1

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  • 核内受容体PXR活性化のマウス肝細胞増殖への影響

    志津怜太, 辺野喜聡, 沼倉裕希, 児玉進, 宮田昌明, 山添康, 吉成浩一

    日本薬学会年会要旨集(CD-ROM)   134th   2014

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  • 構成的に発現しているPXRはCAR依存的な肝細胞増殖を抑制する

    高橋未来, 志津怜太, 辺野喜智, 児玉進, 山添康, 吉成浩一

    日本薬学会年会要旨集(CD-ROM)   134th   2014

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  • Pregnane X receptor protects liver from concanavalin A-induced hepatitis

    SHIMURA Takuto, KODAMA Susumu, KURIBAYASHI Hideaki, MIYATA Masaaki, YOSHINARI Kouichi, YAMAZOE Yasushi

    Annual Meeting of the Japanese Society of Toxicology   40 ( 0 )   2013

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    核内受容体pregnane X receptor (PXR)は，肝臓や腸管に高いレベルで発現し，それら臓器の主要な生理機能の調節を担う低分子応答性の転写因子である。近年，PXRの機能喪失や異常と免疫系の活性亢進及び炎症性疾患との関連，またPXRの活性化による炎症軽減作用が報告され，PXRの新規生理機能として免疫系調節への関与が注目されている。しかし，その詳細な作用機序は依然として不明である。そこでコンカナバリンA(Con A)誘発性マウス肝障害モデルを用いて，PXRによる免疫系調節の作用機序の解明を目的に本研究を実施した。Con Aの単回静脈投与は，肝特異的に障害を誘発する。野生型マウス及びPXR欠損(PXR-KO)マウスにCon Aを同量投与した結果，野生型と比較して，PXR-KOマウスでは肝細胞壊死の増悪化や肝組織内への好中球の浸潤亢進が認められ，これらは血中ALT値の著しい上昇と正に相関していた。次いで，野生型マウスにげっ歯類特異的PXRリガンドPCNを前投与したところ，Con A投与9時間後において有意な肝細胞壊死の軽減，血中ALT値の改善，及び炎症関連遺伝子群のmRNAレベルの低下が認められた。更にCon A投与後，肝細胞壊死や血中ALT値の上昇が認められない早期の段階（3時間後）においては，ケモカインCCL2 やCXCL2のmRNAレベルの有意な上昇や肝組織内への好中球浸潤が認められた一方で，PCNの前投与によりこれらが著しく抑制されることを新たに見出した。以上本研究により，PXRの遺伝子欠損により，マウスのCon A誘発性肝障害に対する感受性が高まること，更にPXR活性化薬の投与は，Con A投与により惹起される一連の免疫反応の過程において，CCL2，CXCL2の発現，肝組織内への好中球の浸潤を抑制し，肝障害を軽減する可能性があることを新たに見出した。

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  • PXR regulates the cell cycle of mouse hepatocytes

    SHIZU Ryota, BENOKI Satoshi, MIYATA Masaaki, KODAMA Susumu, YOSHINARI Kouichi

    Annual Meeting of the Japanese Society of Toxicology   40 ( 0 )   2013

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    核内受容体pregnene X receptor (PXR)およびconstitutive androstane receptor (CAR)は，肝に高発現し，生体異物に応答して異物除去など様々な生理機能を制御する転写因子である。CARの活性化はまた，肝細胞増殖や肝発がんと関連しており，このことが化学物質の安全性評価においてしばしば問題となる。最近我々は，PXRの活性化は単独では肝細胞増殖作用を示さないものの，CAR活性化薬や核内受容体PPARα活性化薬による肝細胞増殖を増強することを見出した（第39回日本毒性学会学術年会）。本研究では，この分子機序を明らかにするために，マウス肝細胞の細胞周期調節におけるPXRの機能を解析した。C57BL/6系雄性マウスにPXR活性化薬物であるpregnenolone 16α-carbonitrile (PCN; 100 mg/kg）を腹腔内投与し，その肝臓を試料として用いた。投与48時間後の肝細胞をコラゲナーゼ灌流法により分離し，propidium iodideによるDNA染色またはPyronin Yおよび7-aminoactinomycin DによるDNA/RNA二重染色を利用したフローサイトサイトメトリー法により細胞周期を解析した結果，PCN投与に伴う肝細胞のG0期からG1期への移行が確認された。また，G0/G1トランジションに関連する遺伝子のmRNAレベルを定量的逆転写PCR法により測定したところ，PCN処置24時間後において，Rbl2 (p130)とその転写調節因子をコードするFoxo1，Foxo3およびFoxo4遺伝子の発現低下が認められた。一方，PXR欠損マウスではそのような変化は認められなかった。さらにレポーターアッセイにおいてPXRの活性化はFOXO3依存的なRbl2の転写を抑制した。またゲルシフトアッセイにおいてPXRはRbl2プロモーター上のFOXO結合領域へのFOXO3の結合を抑制した。以上の結果から，PXRはマウス肝細胞において，FOXO3との相互作用によりRbl2の発現を抑制し，細胞周期をG0期からG1期に移行させることで様々な細胞増殖刺激に対する感受性を増加させる機能を有することが示唆された。

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  • CAR依存的な肝細胞増殖はPXR欠損マウスにおいて増強される

    高橋未来, 志津怜太, 辺野喜智, 児玉進, 山添康, 吉成浩一

    日本薬学会東北支部大会講演要旨集   52nd   2013

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  • PXR activator enhances CAR-dependent hepatocyte proliferation in mice

    SHIZU Ryota, YOSHINARI Koichi, BENOKI Satoshi, KODAMA Susumu, YAMAZOE Yasushi

    Annual Meeting of the Japanese Society of Toxicology   39 ( 0 )   P - 180   2012

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    【目的】Constitutive androstane receptor (CAR)およびpregnene X receptor (PXR)は、肝に高発現し生体異物により活性化される核内受容体である。両受容体は薬物代謝酵素など異物除去と関連する種々の遺伝子の転写制御に中心的に働いている。また、両受容体は類似したプロモーター配列に結合するため、多くの標的遺伝子を共有し、上記の遺伝子発現において協調的に機能していると考えられている。CARは、薬物代謝酵素の誘導に加えて、齧歯動物における肝細胞増殖にも働くことが知られており、CAR活性化作用が化学物質のヒトでの安全性評価において問題となっている。一方、PXRと肝細胞増殖に関する報告はほとんどなく、肝細胞増殖作用における両核内受容体の協調性は明確ではない。本研究では、CARとPXRが、薬物代謝酵素の遺伝子発現と同様に、肝細胞増殖作用においても協調的に機能しているか否かを検討した。【方法】8週齢の雄性C57BL/6系マウスにCAR活性化薬物のTCPOBOP (3 mg/kg)とPXR活性化薬物のPCN (100 mg/kg）を単独または同時に腹腔内投与し、4、24、48時間後の肝臓を試料とした。細胞増殖は抗Ki-67抗体および抗PCNA抗体を用いた免疫染色により評価した。細胞周期関連遺伝子のmRNA発現レベルは定量的逆転写PCR法により測定した。【結果・考察】TCPOBOP処置24および48時間後においてKi-67またはPCNA陽性細胞数の増加、細胞周期関連遺伝子発現レベルの増加が認められ、CARの肝細胞増殖作用が確認された。一方、PCN処置ではいずれの時間においてもそのような変化は認められなかった。しかし、PCNをTCPOBOPと併用処置した場合には、24および48時間後における細胞増殖陽性細胞数や細胞周期関連遺伝子の発現レベルは、TCPOBOP単独処置時に比べて増加した。以上の結果から、マウス肝において、PXRの活性化は、単独では細胞増殖を引き起こさないがCARによる細胞増殖作用を増強させる可能性が示された。

    DOI： 10.14869/toxpt.39.1.0.P-180.0

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  • LIGANDED PXR FACILITATES BINDING OF SERUM/GLUCOCORTICOID REGULATED KINASE 2 ISOFORM ALPHA TO THE G6PASE PROMOTER TO ACTIVATE IT

    Saki Gotoh, Masahiko Negishi, Susumu Kodama

    DRUG METABOLISM REVIEWS   44   33 - 33   2012

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  • The effect of CAR activation on the hepatic expression levels of cell cycle-related gene

    BENOKI Satoshi, YOSHINARI Koichi, SHIZU Ryota, KODAMA Susumu, YAMAZOE Yasushi

    Annual Meeting of the Japanese Society of Toxicology   39 ( 0 )   P - 181   2012

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    【背景・目的】Constitutive androstane receptor (CAR)とpregnane X receptor (PXR)は、同じ核内受容体遺伝子ファミリーに属し、類似した機能を有している。両者は共に肝に高発現し、薬物などの生体外異物により活性化される。CARとPXRが結合する塩基配列は類似しており、異物代謝関連遺伝子など多くの標的遺伝子は両者により活性化される。CARまたはPXRを活性化する薬物はいずれも齧歯動物において肝肥大を起こすことも知られている。しかし、詳細な分子機構は不明であるが、CARの活性化は、齧歯動物において肝細胞増殖作用を示すのに対し、PXRの活性化は肝細胞増殖および肝発癌プロモーション作用を示さないと考えられている。このため、CAR選択的な発現制御を受ける遺伝子が肝細胞増殖作用に関わるのではないかと考えた。そこで本研究では、CARまたはPXRの活性化に伴う、細胞周期関連遺伝子の発現プロファイルの変化を比較解析した。【方法】8週齢の雄性C57BL/6NマウスにマウスCAR活性化物質のTCPOBOP (3 mg/kg)、マウスPXR活性化物質のPCN (100 mg/kg)または溶媒を経時的に投与し、肝から調製したRNAを用いて、PCRアレイ法 (細胞周期関連の84遺伝子)および定量的逆転写PCR法により細胞周期関連遺伝子の発現変動を解析した。【結果・考察】TCPOBOPとPCN投与に伴う細胞周期関連遺伝子の発現変動プロファイルは大きく異なることが示され、CAR選択的に発現が制御されている可能性がある遺伝子を7遺伝子同定した。その中にはNek2やCdc20などのG2期からM期への移行に関与する遺伝子が含まれており、これらの遺伝子の発現変動がCARを介した肝細胞増殖に関与している可能性が考えられた。

    DOI： 10.14869/toxpt.39.1.0.P-181.0

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  • Nuclear receptor PXR Elicits p38 MAPK signal via activation of the GADD45 beta gene

    Susumu Kodama, Masahiko Negishi

    DRUG METABOLISM REVIEWS   41   171 - 171   2009.10

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  • 組換え型AhR/GUS遺伝子系を導入した形質転換植物におけるダイオキシン類のバイオアッセイ

    川畑順子, 祇園景子, 児玉進, 乾秀之, 大川秀郎

    日本農芸化学会大会講演要旨集   2006   2006

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

    S Kodama, C Koike, Y Yamamoto, M Negishi

    DRUG METABOLISM REVIEWS   36   311 - 311   2004.8

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  • チトクロームP450の分子機能を難分解性有機汚染物質のモニタリングや負荷軽減へ応用する

    KODAMA Susumu, INUI Hideyuki, OHKAWA Hideo

    化学と生物   41 7 464-470 ( 7 )   464 - 470   2003

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  • Herbicide-Metabolism and Cross-Tolerance in Transgenic Tobacco Plants Expressing Human CYP2C19

    KODAMA Susumu, SHIOTA Noriaki, INUI Hideyuki, OHKAWA Hideo

    24   50 - 50   1999.3

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Research Projects

  • より現実的な化学物質のリスク評価を目指した生体異物センサー機能調節機序の解明

    2019.04

    日本学術振興会  科学研究費助成事業 基盤研究（C） 

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  • 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

    2016.04 - 2019.03

    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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  • 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

    2015.04 - 2018.03

    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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  • 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

    2014.04 - 2017.03

    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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  • 核内受容体PXRの新規生理機能:免疫メンテナンスの解明

    2012.04 - 2014.03

    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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  • 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

    2012.04 - 2013.03

    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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  • Biological Chemistry 3 （2023academic year） Third semester  - 金5～6

  • Biological Chemistry 3 （2023academic year） Third semester  - 金5～6

  • Biological Chemistry 4 （2023academic year） Fourth semester  - 金3～4

  • Biological Chemistry 4 （2023academic year） Fourth semester  - 金3～4

  • Biological Chemistry C （2023academic year） 3rd and 4th semester  - [第３学期]金5～6, [第４学期]金3～4

  • Biological Chemistry C （2023academic year） 3rd and 4th semester  - [第３学期]金5～6, [第４学期]金3～4

  • Practice in Hygienic Pharmaceutical Sciences （2023academic year） 2nd and 3rd semester  - その他5～9

  • Practice in Hygienic Pharmaceutical Sciences （2023academic year） 2nd and 3rd semester  - その他5～9

  • Practice in Hygienic Pharmaceutical Sciences （2023academic year） 2nd and 3rd semester  - その他5～9

  • Practice in Hygienic Pharmaceutical Sciences （2023academic year） 2nd and 3rd semester  - その他5～9

  • Introduction to Communication for Pharmaceutical Sciences （2022academic year） 1st semester  - 火3～4

  • Introduction to Communication for Pharmaceutical Sciences （2022academic year） 1st semester  - 火3～4

  • Regulatory Science （2022academic year） Fourth semester  - 月7～8

  • Regulatory Science （2022academic year） Fourth semester  - 月7～8

  • Regulatory Science （2022academic year） Fourth semester  - 月7～8

  • Regulatory Science （2022academic year） Fourth semester  - 月7～8

  • Are chemical substances dangerous for you ? （2022academic year） Third semester  - 火3～4

  • Toxicology （2022academic year） special  - その他

  • Life Science 2 （2022academic year） special  - その他

  • Biological Chemistry 3 （2022academic year） Third semester  - 金5～6

  • Biological Chemistry 3 （2022academic year） Third semester  - 金5～6

  • Biological Chemistry 4 （2022academic year） Fourth semester  - 金3～4

  • Biological Chemistry 4 （2022academic year） Fourth semester  - 金3～4

  • Biological Chemistry C （2022academic year） 3rd and 4th semester  - [第３学期]金5～6, [第４学期]金3～4

  • Biological Chemistry C （2022academic year） 3rd and 4th semester  - [第３学期]金5～6, [第４学期]金3～4

  • Practice in Hygienic Pharmaceutical Sciences （2022academic year） 2nd and 3rd semester  - その他5～9

  • Practice in Hygienic Pharmaceutical Sciences （2022academic year） 2nd and 3rd semester  - その他5～9

  • Introduction to Communication for Pharmaceutical Sciences （2021academic year） 1st semester  - 火3～4

  • Introduction to Communication for Pharmaceutical Sciences （2021academic year） 1st semester  - 火3～4

  • Regulatory Science （2021academic year） Fourth semester  - 木7～8

  • Regulatory Science （2021academic year） Fourth semester  - 木7～8

  • Are chemical substances dangerous for you ? （2021academic year） Third semester  - 金3～4

  • Toxicology （2021academic year） special  - その他

  • Life Science 2 （2021academic year） Late  - その他

  • Biological Chemistry 3 （2021academic year） Third semester  - 金5,金6

  • Biological Chemistry 3 （2021academic year） Third semester  - 金5,金6

  • Biological Chemistry 4 （2021academic year） Fourth semester  - 金3,金4

  • Biological Chemistry 4 （2021academic year） Fourth semester  - 金3,金4

  • Biological Chemistry C （2021academic year） 3rd and 4th semester  - [第３学期]金5,金6, [第４学期]金3,金4

  • Biological Chemistry C （2021academic year） 3rd and 4th semester  - [第３学期]金5,金6, [第４学期]金3,金4

  • Basic Practice in Pharmaceutical Sciences （2021academic year） 1-3 semesters  - その他6～9

  • Basic Practice in Pharmaceutical Sciences （2021academic year） 1-3 semesters  - その他6～9

  • Practice in Hygienic Pharmaceutical Sciences （2021academic year） Third semester  - その他6～9

  • Practice in Hygienic Pharmaceutical Sciences （2021academic year） Third semester  - その他6～9

  • Introduction to Communication for Pharmaceutical Sciences （2020academic year） Fourth semester  - 火7,火8

  • Regulatory Science （2020academic year） Fourth semester  - 月3,月4

  • Regulatory Science （2020academic year） Fourth semester  - 月3,月4

  • Are chemical substances dangerous for you ? （2020academic year） Third semester  - 金3,金4

  • Toxicology （2020academic year） special  - その他

  • Life Science 2 （2020academic year） special  - その他

  • Biological Chemistry 3 （2020academic year） Third semester  - 火7,火8

  • Biological Chemistry 3 （2020academic year） Third semester  - 火7,火8

  • Biological Chemistry 4 （2020academic year） Fourth semester  - 水1,水2

  • Biological Chemistry 4 （2020academic year） Fourth semester  - 水1,水2

  • Basic Practice in Pharmaceutical Sciences （2020academic year） special  - その他

  • Basic Practice in Pharmaceutical Sciences （2020academic year） special  - その他

  • Practice in Hygienic Pharmaceutical Sciences （2020academic year） special  - その他

  • Practice in Hygienic Pharmaceutical Sciences （2020academic year） special  - その他

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