Study for mechanisms of drug-induced severe cutaneous reactions

• Project/Area Number: 15K19168
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Applied pharmacology
• Research Institution: National Institute of Health Sciences
• Principal Investigator: Okamoto-Uchida Yoshimi 国立医薬品食品衛生研究所, 医薬安全科学部, 任期付研究員 (40716792)
• Research Collaborator: Kanoh Naoki 東北大学, 東北大学大学院薬学研究科, 准教授
• Project Period (FY): 2015-03-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: スティーブンス・ジョンソン症候群 / 中毒性表皮壊死症 / HLA / 医薬品 / 分子間相互作用 / 副作用 / ヒト白血球抗原

Outline of Final Research Achievements

Recent studies have revealed that the prevalence of Stevens-Johnson Syndrome/ Toxic Epidermal Necrolysis (SJS/TEN) is associated with genetic backgrounds, such as polymorphisms in human leukocyte antigens (HLAs). However, molecular mechanism involved in the SJS/TEN onset has been largely unknown. In this project, we developed a system for determination of affinity between drug and HLA protein. This system would be useful for estimation of drug adverse reactions.

Research Products

• [Int'l Joint Research] Chang Gung Memorial Hospital(Taiwan)
• [Int'l Joint Research] Institute of Biomedical Sciences/Chung Gung Memorial Hospital(Taiwan)
• [Journal Article] The mevalonate pathway regulates primitive streak formation via protein farnesylation (2016)
  • Author(s): Okamoto-Uchida Y, Yu R, Miyamura N, Arima N, Ishigami-Yuasa M, Kagechika H, Yoshida S, Hosoya T, Nawa M, Kasama T, Asaoka Y, Alois RW, Elling U, Penninger JM, Nishina S, Azuma N, Nishina H
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 37697-37697
  • DOI: 10.1038/srep37697
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Different Results of IgE Binding- and Crosslinking-Based Allergy Tests Caused by Allergen Immobilization (2016)
  • Author(s): Okamoto-Uchida Y, Nakamura R, Matsuzawa Y, Soma M, Kawakami H, Ishii-Watabe A, Nishimaki-Mogami T, Teshima R, Saito Y.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 39 Issue: 10 Pages: 1662-1666
  • DOI: 10.1248/bpb.b16-00389
  • NAID: 130005598496
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed / Open Access
• [Journal Article] Drugs causing severe ocular surface involvements in Japanese patients with StevenseJohnson syndrome/toxic epidermal necrolysis (2015)
  • Author(s): Kaniwa N, Ueta M, Nakamura R, Okamoto-Uchida Y, Sugiyama E, Maekawa K, Takahashi Y, Furuya H, Yagami A, Matsukura S, Ikezawa Z, Matsunaga K, Sotozono C, Aihara M, Kinoshita S, Saito Y.
  • Journal Title: Allergology International Volume: 64 Issue: 4 Pages: 379-381
  • DOI: 10.1016/j.alit.2015.05.002
  • NAID: 130005290406
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Use of Humanized Rat Basophilic Leukemia Reporter Cell Lines as a Diagnostic Tool for Detection of Allergen-Specific IgE in Allergic Patients: Time for a Reappraisal? (2015)
  • Author(s): Falcone FH, Alcocer MJC, Okamoto-Uchida Y, Nakamura R
  • Journal Title: Curr Allergy Asthma Rep. Volume: 15 Issue: 11 Pages: 67-67
  • DOI: 10.1007/s11882-015-0568-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development of a simple genotyping method for the HLA-A∗31:01-tagging SNP in Japanese (2015)
  • Author(s): Maekawa K, Nakamura R, Kaniwa N, Mizusawa S, Kitamoto A, Kitamoto T, Ukaji M, Matsuzawa Y, Sugiyama E, Uchida Y, Kurose K, Ueta M, Sotozono C, Ikeda H, Yagami A, Matsukura S, Kinoshita S, Muramatsu M, Ikezawa Z, Sekine A, Furuya H, Takahashi Y, Matsunaga K, Aihara M, Saito Y
  • Journal Title: Pharmacogenomics. Volume: 16 Issue: 15 Pages: 1689
  • DOI: 10.2217/pgs.15.115
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Modified Murine Embryonic Stem Cell Test for Evaluating the Teratogenic Effects of Drugs on Early Embryogenesis (2015)
  • Author(s): Ruoxing Yu, Norio Miyamura, Yoshimi Okamoto-Uchida, Norie Arima, Mari Ishigami-Yuasa, Hiroyuki Kagechika and Hiroshi Nishina
  • Journal Title: PLoS ONE Volume: 10 Issue: 12 Pages: e0145286-e0145286
  • DOI: 10.1371/journal.pone.0145286
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 臨床における重症薬疹とゲノムマーカー (2015)
  • Author(s): 岡本（内田）好海、児玉進、中村亮介、斎藤嘉朗
  • Journal Title: 毒性質問箱 Volume: 17 Pages: 18-23
  • Acknowledgement Compliant
• [Presentation] The mevalonate pathway regulates primitive streak formation via protein farnesylation (2017)
  • Author(s): Ruoxing Yu, Yoshimi Okamoto-Uchida, Hiroshi Nishina
  • Organizer: 日本薬学会第137回年会
  • Place of Presentation: 仙台
  • Year and Date: 2017-03-24
• [Presentation] Involvement of Infectious Diseases in Pathogenesis of Stevens -Johnson Syndrome and Toxic Epidermal Necrolysis. (2017)
  • Author(s): Yoshimi Okamoto-Uchida, Ryosuke Nakamura, Kimie Sai, Takuya Imatoh, Kayoko Matsunaga, Michiko Aihara, Yoshiro Saito
  • Organizer: International Stevens-Johnson syndrome symposium
  • Place of Presentation: Kyoto
  • Year and Date: 2017-01-21
  • Int'l Joint Research
• [Presentation] スティーブンスジョンソン症候群・中毒性壊死症における感染症併発の影響 (2016)
  • Author(s): 岡本(内田) 好海、中村亮介、佐井君江、今任拓也、松永佳代子、相原道子、斎藤嘉朗
  • Organizer: 第23回日本免疫毒性学会年会
  • Place of Presentation: 北九州
  • Year and Date: 2016-09-06
• [Presentation] セルベーストアッセイによる牛肉アレルギー患者血清中IgEの糖鎖抗原への反応性の解析 (2016)
  • Author(s): 岡本(内田)好海, 中村亮介, 千貫祐子, 若林翼, 打田光宏, 土屋敏行, 斎藤嘉朗, 森田栄伸
  • Organizer: 日本薬学会第136年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-03-26
• [Presentation] Drugs and HLA types associated with Stevens–Johnson syndrome/toxic epidermal necrolysis with severe ocular surface involvements in Japanese patients (2016)
  • Author(s): Nakamura R, Kaniwa N, Ueta M, Okamoto-Uchida Y, Sugiyama E, Maekawa K, Takahashi Y, Furuya H, Yagami A, Matsukura S, Ikezawa Z, Matsunaga K, Tokunaga K, Sotozono C, Aihara M, Kinoshita S, Saito Y.
  • Organizer: 1st Internati- onal Stevens- Johnson Syndrome Symposium
  • Place of Presentation: 京都
  • Year and Date: 2016-01-23
• [Presentation] スティーブンス・ジョンソン症候群/中毒性表皮壊死症の病態に対する感染症の影響 (2016)
  • Author(s): 岡本（内田)好海、中村亮介、佐井君江、今任拓也、松永佳世子、相原道子、斎藤嘉朗
  • Organizer: 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
  • Place of Presentation: 東京
• [Presentation] 中村亮介, 岡本(内田)好海, 松澤由美子, 石井明子, 斎藤嘉朗 (2015)
  • Author(s): EXiLE法を用いたモデル抗原のIgEエピトープ解析
  • Organizer: 第22回日本免疫毒性学会学術年会
  • Place of Presentation: 京都
  • Year and Date: 2015-09-10
• [Presentation] 重篤副作用発症における感染症併発の影響 ― 横紋筋融解症及び重症薬疹の事例 ― (2015)
  • Author(s): 佐井君江, 中村亮介, 今任拓也, 岡本好海, 梶波康二, 松永佳世子, 相原道子, 斎藤嘉朗
  • Organizer: 第42回日本毒性学会学術年会
  • Place of Presentation: 金沢
  • Year and Date: 2015-06-29
• [Presentation] 重症眼粘膜障害を伴うSJS/TENの発症と関連する被疑薬およびHLA型について (2015)
  • Author(s): 中村亮介, 鹿庭なほ子,上田真由美, 岡本(内田)好海, 杉山永見子, 高橋幸利, 古谷博和, 矢上晶子, 松倉節子, 池澤善郎, 松永佳世子, 徳永勝士, 外園千恵, 相原道子, 木下茂, 斎藤嘉朗
  • Organizer: 第64回日本アレルギー学会学術大会
  • Place of Presentation: 東京
  • Year and Date: 2015-05-26