Study on the possible mechanism for the polychlorinated biphenyl-induced liver-selective accumulation of thyroxine

• Project/Area Number: 26340043
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Risk sciences of radiation and chemicals
• Research Institution: Tokushima Bunri University
• Principal Investigator: Kato Yoshihisa 徳島文理大学, 薬学部, 教授 (90161132)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 甲状腺ホルモン撹乱 / サイロキシン / PCB / 肝臓 / トランスポーター / マウス / Kanechlor-500 / 肝実質細胞 / 小腸 / グルクロン酸抱合酵素 / ラット / ヒト

Outline of Final Research Achievements

We strongly suggested that the decrease in serum thyroxine (T4) level caused by exposure to polychlorinated biphenyls (PCBs) occurs mainly through increased accumulation of T4 in the liver. We suggested that the PCB-mediated liver-selective accumulation of T4 might occur, at least in part, through the increased expression of T4 influx transporters, such as LAT1 and oatp2. We further suggested that the PCB-mediated decrease in serum T4 levels occurs through the enhanced hepatic accumulation of T4 and, at least in part, through increases in the Mrp3-mediated excretion of T4 conjugate(s), not only through the induction of T4- UDP-glucuronosyltransferase. Further studies on the effects of PCBs on hepatic T4-transporters would be necessary to understand the exact mechanism for the PCB-induced decrease in serum T4 level.

Research Products

• [Journal Article] Induction of hepatic T4 transporters by polychlorinated biphenyl in rats. (2016)
  • Author(s): Yoshihisa Kato, Koichi Haraguchi, Aki Fujii, Yukiko Fujii, Osamu Kimura, Chiho Ohta, Tetsuya Endo, Nobuyuki Koga, Shizuo Yamada, and Masakuni Degawa
  • Journal Title: Organohalogen Compounds Volume: 78 Pages: 873-876
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Metabolism of 2,2',3,4,4',5,6'- heptachlorobiphenyl (CB182) by rat, guinea pig and human liver microsomes. (2016)
  • Author(s): Chiho Ohta, Yukiko Fujii, Koichi Haraguchi, Yoshihisa Kato, Osamu Kimura, Tetsuya Endo, Nobuyuki Koga
  • Journal Title: Organohalogen Compounds Volume: 78 Pages: 870-872
  • NAID: 120006318699
  • Peer Reviewed
• [Journal Article] Effect of quercetin on the uptake and efflux of aristolochic acid I from Caco-2 cell monolayers (2016)
  • Author(s): Kimura, O., Fujii, Y., Haraguchi, K., Ohta, C., Koga, N., Kato, Y., Endo, T
  • Journal Title: Journal of Pharmacy and Pharmacology. Volume: - Issue: 7 Pages: 2042-7158
  • DOI: 10.1111/jphp.12557
  • Peer Reviewed / Open Access
• [Journal Article] Metal Concentrations in the Liver and Stable Isotope Ratios of Carbon and Nitrogen in the Muscle of Silvertip Shark (Carcharhinus albimarginatus) Culled off Ishigaki Island, Japan (2016)
  • Author(s): Endo, T., Kimura, O., Ohta, C., Koga, N., Kato, Y., Fujii, Y., Haraguchi, K.
  • Journal Title: PLoS One Volume: 11 Issue: 2 Pages: 1-18
  • DOI: 10.1371/journal.pone.0147797
  • Peer Reviewed / Open Access
• [Journal Article] Distribution and excretion of 2,2',3,4',5,5',6-heptachlorobiphenyl (CB187) and its metabolites in rats and guinea pigs (2015)
  • Author(s): Chiho Ohta, Koichi Haraguchi, Yoshihisa Kato, Tetsuya Endo, Osamu Kimura, Nobuyuki Koga
  • Journal Title: Chemosphere Volume: 118 Pages: 5-11
  • DOI: 10.1016/j.chemosphere.2014.05.019
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] 2,2',3,4',4,5,5'-七塩素化ビフェニル（CB180）の動物肝ミクロゾームによる代謝. (2015)
  • Author(s): 太田千穂、原口浩一、加藤善久、遠藤哲也、木村 治、古賀信幸
  • Journal Title: 福岡医学雑誌 Volume: 106 Pages: 176-183
  • Acknowledgement Compliant
• [Journal Article] Mercury, cadmium, zinc and copper concentrations and stable isotope ratios of carbon and nitrogen in tiger sharks (Galeocerdo cuvier) culled off Ishigaki Island, Japan. (2015)
  • Author(s): Tetsuya Endo, Osamu Kimura, Hideki Ogasawara, Chiho Ohta, Nobuyuki Koga, Yoshihisa Kato, Koichi Haraguchi
  • Journal Title: Ecol. Indic. Volume: 55 Pages: 86-93
  • DOI: 10.1016/j.ecolind.2015.03.008
  • Peer Reviewed
• [Journal Article] Cyclosporin A-sensitive cytotoxicity of flurbiprofen nonstereoselectively mediated by cytochrome P450 metabolism in three-dimensional cultured rat hepatocytes. (2015)
  • Author(s): Tadatoshi Tanino, Yoshinori Funakami, Noriaki Nagai, Yoshihisa Kato
  • Journal Title: Journal of Pharmacy and Pharmacology Volume: 67 Issue: 10 Pages: 1406-1415
  • DOI: 10.1111/jphp.12443
  • Peer Reviewed
• [Journal Article] 3,3′,4,4′-Tetrachlorobiphenyl-Mediated Decrease of Serum Thyroxine Level in C57BL/6 and DBA/2 Mice Occurs Mainly through Enhanced Accumulation of Thyroxine in the Liver (2014)
  • Author(s): Yoshihisa Kato, Koichi Haraguchi, Mao Onishi, Shinichi Ikushiro, Tetsuya Endo, Chiho Ohta, Nobuyuki Koga, Shizuo Yamada, and Masakuni Degawa
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 37 Issue: 3 Pages: 504-509
  • DOI: 10.1248/bpb.b13-00775
  • NAID: 130003382126
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Dietary exposure to phenolic and methoxylated organohalogen contamin ants in relation to their concentrations in breast milk and serum in Ja pan. (2014)
  • Author(s): Fuiii, Y. ; Nishimura, E. ; Kato, Y . ; Harada, K. H. ; Koizumi, A. ; Haraguchi, K.
  • Journal Title: Environ Int Volume: 63 Pages: 19-25
  • DOI: 10.1016/j.envint.2013.10.016
  • Peer Reviewed
• [Journal Article] Carrier-mediated uptake of Nobiletin, a citrus polymethoxyflavonoid, in human intestinal Caco-2 cells (2014)
  • Author(s): Osamu Kimura, Chiho Ohta, Nobuyuki Koga, Koichi Haraguchi, Yoshihisa Kato, and Tetsuya Endo
  • Journal Title: Food Chemistry Volume: 154 Pages: 145-150
  • DOI: 10.1016/j.foodchem.2013.12.069
  • Peer Reviewed
• [Journal Article] The participation of rat CYP3A enzymes in the metabolism of 2,2',4,5,5'-pentachlorobiphenyl (CB101) (2014)
  • Author(s): Chiho Ohta, Koichi Haraguchi, Yoshihisa Kato, Tetsuya Endo, Nobuyuki Koga
  • Journal Title: Organohalogen Compounds Volume: 76 Pages: 466-469
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Uptake of Aristolochic Acid I into Caco-2 Cells by Monocarboxylic Acid Transporters (2014)
  • Author(s): Osamu Kimura, Koichi Haraguchi, Chiho Ohta, Nobuyuki Koga, Yoshihisa Kato, Tetsuya Endo
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 37 Issue: 9 Pages: 1475-1479
  • DOI: 10.1248/bpb.b14-00219
  • NAID: 130004684786
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed
• [Presentation] Caco-2細胞におけるぺルフルオロオクタン酸の取り込み (2017)
  • Author(s): 木村 治，藤井由希子，原口浩一，加藤善久，太田千穂，古賀信幸，遠藤哲也
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 仙台国際センター、仙台
  • Year and Date: 2017-03-24
• [Presentation] 2,2',3,4,4',5,6'-七塩素化ビフェニル(CB182)の動物およびヒト肝ミクロゾームによる代謝 (2017)
  • Author(s): 太田千穂, 藤井由希子, 原口浩一, 加藤善久, 木村 治, 遠藤哲也, 古賀信幸
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 仙台国際センター、仙台
  • Year and Date: 2017-03-24
• [Presentation] Induction of hepatic T4 transporters by polychlorinated biphenyl in rats. (2016)
  • Author(s): Kato, Y., Haraguchi, K., Fujii, A., Fujii, Y., Kimura, O., Ohta, C., Endo, T., Koga, N., Yamada, S., Degawa, M.
  • Organizer: 36th International Symposium on Halogenated Persistent Organic Pollutants
  • Place of Presentation: Firenze, Italy
  • Year and Date: 2016-08-28
  • Int'l Joint Research
• [Presentation] Metabolism of 2,2',3,4,4',5,6'- heptachlorobiphenyl (CB182) by rat, guinea pig and human liver microsomes. (2016)
  • Author(s): Ohta, C., Fujii, Y., Haraguchi, K., Kato, Y., Kimura, O., Endo, T., and Koga, N.
  • Organizer: 36th International Symposium on Halogenated Persistent Organic Pollutants
  • Place of Presentation: Firenze, Italy
  • Year and Date: 2016-08-28
  • Int'l Joint Research
• [Presentation] Caco-2細胞におけるアリストロキア酸Iの膜透過に及ぼすケルセチンの影響 (2016)
  • Author(s): 木村 治，藤井由希子，原口浩一，太田千穂，古賀信幸，加藤善久，遠藤哲也
  • Organizer: 日本薬学会第136年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-03-26
• [Presentation] 大型海洋ほ乳類を用いた有機フッ素化合物の肝臓蓄積実態の解明 (2016)
  • Author(s): 木下真璃伽，久我歩佳，藤井由希子，加藤善久，木村 治，遠藤哲也，太田千穂，古賀信幸，原口浩一
  • Organizer: 日本薬学会第136年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-03-26
• [Presentation] 化学物質による血中甲状腺ホルモン濃度低下作用機構の薬物動態学的解明 (2016)
  • Author(s): 加藤善久
  • Organizer: 第2回バイオシグナル研究会
  • Place of Presentation: 神戸大学、神戸
• [Presentation] 医薬品や化学物質による血中甲状腺ホルモン濃度低下作用機構の解明 (2015)
  • Author(s): 加藤善久
  • Organizer: 静薬学友会四国支部大会
  • Place of Presentation: 徳島
  • Year and Date: 2015-11-29
• [Presentation] 海洋生物由来臭素化合物のヒト肝酵素による代謝 (2015)
  • Author(s): 太田千穂，西村恵理，原口浩一，遠藤哲也，加藤善久，山本健太，古賀信幸
  • Organizer: フォーラム2015：衛生薬学・環境トキシコロジー
  • Place of Presentation: 神戸
  • Year and Date: 2015-09-17
• [Presentation] PCBによる血中甲状腺ホルモン濃度低下作用機構の解明 (2015)
  • Author(s): 加藤善久
  • Organizer: 第3回 PCB講演会
  • Place of Presentation: 神戸
  • Year and Date: 2015-07-31
• [Presentation] 海洋生物由来のTetrabromo-1,4-dimethoxybenzene (TDB)の動物肝ミクロゾームによる代謝 (2015)
  • Author(s): 太田千穂，西村恵理，原口浩一，遠藤哲也，加藤善久，山本健太，古賀信幸
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 神戸
  • Year and Date: 2015-03-25 – 2015-03-28
• [Presentation] Contamination trends of hexabromocyclododecanes, tribromophenol and tetrabromobisphenol a in Japanese breast milk (2015)
  • Author(s): Koichi Haraguchi, Yukiko Fujii, Yoshihisa Kato, Tetsuya Endo
  • Organizer: 54th The exposition of the Society of Toxicology Annual Meeting
  • Place of Presentation: San Diego, California, USA
  • Year and Date: 2015-03-22 – 2015-03-26
• [Presentation] 海洋生物由来2,2'-dimethoxy-BB80のラットにおけるin vivo代謝 (2014)
  • Author(s): 西村恵理，太田千穂，原口浩一，遠藤哲也，加藤善久，山本健太，古賀信幸
  • Organizer: フォーラム2014：衛生薬学・環境トキシコロジー
  • Place of Presentation: つくば
  • Year and Date: 2014-09-19 – 2014-09-20
• [Presentation] The participation of rat CYP3A enzymes in the metabolism of 2,2',4,5,5'-pentachlorobiphenyl (CB101) (2014)
  • Author(s): Chiho Ohta, Koichi Haraguchi, Yoshihisa Kato, Tetsuya Endo, Nobuyuki Koga
  • Organizer: 34th International Symposium on Halogenated Persistent Organic Pollutants
  • Place of Presentation: Madrid, Spain
  • Year and Date: 2014-08-31 – 2014-09-05
• [Presentation] Kaempferol tetramethyleherのラット肝ミクロゾームによる代謝 (2014)
  • Author(s): 山本健太，緒方 瞳，太田千穂，原口浩一，遠藤哲也，西村恵理，木村 修，加藤善久，古賀信幸
  • Organizer: 第68回日本栄養・食糧学会大会
  • Place of Presentation: 江別
  • Year and Date: 2014-05-30 – 2014-06-01
• [Remarks] 徳島文理大学香川薬学部薬物動態学講座
  • URL: http://kp.bunri-u.ac.jp/kph17/index.html
• [Remarks] 徳島文理大学 香川薬学部 薬物動態学講座
  • URL: http://kp.bunri-u.ac.jp/kph17/index.html