2000 Fiscal Year Annual Research Report

薬物代謝酵素の遺伝的多型:日本人に見られる新規多型の解析と遺伝子診断法の開発

Research Project

Project/Area Number	10557242
Research Institution	HOKKAIDO UNIVERSITY
Principal Investigator	有吉範高北海道大学, 大学院・薬学研究科, 助教授 (00243957)
Co-Investigator(Kenkyū-buntansha)	中山佳都夫北海道大学, 大学院・薬学研究科, 助手 (20261323) 高橋芳樹北海道大学, 大学院・薬学研究科, 助手 (80292019) 藤田健一北海道大学, 大学院・薬学研究科, 助手 (60281820) 峯毅住友製薬(株), 総合研究開発研究所, 主任研究員鎌滝哲也北海道大学, 大学院・薬学研究科, 教授 (00009177)
Keywords	薬物代謝 / チトクロームP450 / CYP2D6 / 遺伝的多型 / poor metabolizer / 薬の効きすぎ / 遺伝子解析 / CYP2D6*36
Research Abstract	CYP2D6は,精神科領域,心血管領域の薬,および抗ヒスタミン薬など,臨床に用いられる多くの重要な薬物の代謝に関与するチトクロームP450(CYP)分子種である.CYP2D6活性を遺伝的に欠損しているヒト(PM)ではCYP2D6で代謝されるべき薬物が代謝されないため,常用量の投与でも血中濃度の異常な上昇が起こり,効きすぎにともなう有害作用が引き起こされる.申請者らは日本人のPMは欧米人のPMと異なる原因遺伝子多型を有していることを明らかにしてきた.昨年度は,日本人PMより新規な遺伝的多型として,CYP2D636(旧名10C)をタンデムで有するCYP2D636-36を見出した.この多型は日本人におけるPMの原因多型の1つと考えられるが,日本人PMのどの程度をこの多型で説明できるかがわかれば,少なくともこの多型によってPMとなっている患者を遺伝子診断で判定し,副作用を回避させることが可能である.そこで,当該多型の遺伝子診断法を開発し,インフォームドコンセントを得た149名の日本人健常者における本多型の頻度を検討した.しかし今回調べた検体中に本多型を有するヒトは1名も見出すことができなかった.日本人ではPMの頻度が1%未満であるため,今回の検体中にはPM自体が1名いるかいないかの程度である.したがって,さらに大きな集団を用いた解析を行い,多くのPMを解析する必要がある.我々は別の集団でこれまでに少なくとも本多型を有する被検者2名を見出している.さらに最近,国内の他の研究グループでも我々の見出した多型を有する検体を見出し,抗不整脈薬であるメキシレチンの代謝が明らかに低いことが報告された.以上のことから,申請者らが日本人において見出したCYP2D636-36はヘテロ接合体であってもある種の薬物の代謝に影響すると考えられる.頻度に関しても中では比較的高い可能性が考えられるため,早急に本多型の頻度を明確にし,医療の現場に還元する必要があると考えられる.

Research Products
(20 results)

All Other

All Publications (20 results)

[Publications] Noritaka Ariyoshi et al.: "A Single Nucleotide Polymorphism of CYP2B6 Found in Japanese Enhances Catalytic Activity by Autoactivation."Biochemical Biophysical Research Communications. (In press). (2001)
[Publications] Noritaka Ariyoshi et al.: "A Novel Single Nucleotide Polymorphism Altering Stability and Activity of CYP2A6."Biochemical Biophysical Research Communications. (In press). (2001)
[Publications] Takeshi Ozeki et al.: "Cooperative regulation of the transcription of human dihydrodiol dehydrogenase (DD) 4/AKR1C4 gene by hepatocyte neclear factor (HNF) -4α/γ and HNF-1α."Biochemical Journal. (In press). (2001)
[Publications] Noritaka Ariyoshi et al.: "Pharmacogenetics on cancer chemotherapy : from basic studies."Japanese Journal of Clinical Pharmacology and Therapeutics. (In press). (2001)
[Publications] Taisei Mushiroda et al.: "Accumulation of the 1-methyl-4-phenylpyridinium ion (MPP+) in suncus (Suncus murinus) brain : Implication for flavin-containing monooxygenase activity in brain microvessels."Chemical Research in Toxicology. (In press). (2001)
[Publications] Loriot, M-A et al.: "Genetic polymorphism of cytochrome P450 2A6 in a case control study on lung cancer in a French population."Pharmacogenetics. 11. 39-44 (2001)
[Publications] Noritaka Ariyoshi et al.: "Studies on the genetic polymorphism of CYP2A6."Drug Metabolism and Disposition. 15. 57-61 (2000)
[Publications] Hirotaka Kushida et al.: "Development of a Salmonella tester strain sensitive to promutagenic N-nitrosamines : expression of recombinant CYP2A6 and human NADPH-cytochrome P450 reductase in S.typhimurium YG7108."Mutation Research. 471. 135-143 (2000)
[Publications] Takashi Satoh et al.: "Studies on the interactions between drugs and estrogen. Analytical method for prediction system of gynecomastia induced by drugs on the inhibitory metabolism of estradiol using Escherichia coli co-expressing human CYP3A4 with human NADPH-cytochrome P450 reductase."Analytical Biochemistry. 286. 179-186 (2000)
[Publications] Noritaka Ariyoshi et al.: "Structural characterization of a new variant of the CYP2A6 gene (CYP2A6*1B) apparently diagnosed as heterozygotes of CYP2A6*1A and CYP2A6*4C."Pharmacogenetics. 10. 678-693 (2000)
[Publications] Taisei Mushiroda et al.: "The house musk shrew (Suncus murinus) : a unique animal with extremely low level of expression of mRNA for CYP3A and flavin-containing monooxygenase."Comparative Biochemistry & Physiology. 126. 225-234 (2000)
[Publications] Hirotaka Kushida et al.: "Metabolic activation of N-alkylnitrosamines in genetically engineered Salmonella typhimurium expressing CYP2E1 or CYP2A6 together with human NADPH-cytochrome P450 reductase."Carcinogenesis. 21. 1227-1232 (2000)
[Publications] Eri Inoue et al.: "Development of bacterial expression system with high yield of CYP3A7, a human fetus-specific form of Cytochrome P450."Biochemical Biophysical Research Communications. 269. 623-627 (2000)
[Publications] Taisei Mushiroda et al.: "A high level expression of CYP2A in the lung of the Suncus (Suncus murinus) and its role in the Activation of 4- (methylntirosamino) -1- (3-pyridyl) -1-butanone (NNK)."Biochemical Biophysical Research Communications. 269. 393-396 (2000)
[Publications] Ken-ichi Fujita et al.: "Establishment of Salmonella strain expressing catalytically active human UDP-glucuronosyltransferase 1A1 (UGT1A1)."Life Science. 66. 1955-1967 (2000)
[Publications] Noritaka Ariyoshi et al.: "Handbook of Experimental Pharmacology"Springer-VerlagBerlin. (2001)
[Publications] 有吉範高: "月刊薬事2001年臨時増刊号"じほう. (2001)
[Publications] 鎌滝哲也: "薬物療法学"南江堂. (2001)
[Publications] 有吉範高: "月刊薬事3月臨時増刊号"じほう. 834 (2000)
[Publications] 鎌滝哲也: "薬物代謝学"東京化学同人. 282 (2000)

2000 Fiscal Year Annual Research Report

薬物代謝酵素の遺伝的多型:日本人に見られる新規多型の解析と遺伝子診断法の開発

Principal Investigator

有吉 範高 北海道大学, 大学院・薬学研究科, 助教授 (00243957)

Research Products

[Publications] Noritaka Ariyoshi et al.: "A Single Nucleotide Polymorphism of CYP2B6 Found in Japanese Enhances Catalytic Activity by Autoactivation."Biochemical Biophysical Research Communications. (In press). (2001)

[Publications] Noritaka Ariyoshi et al.: "A Novel Single Nucleotide Polymorphism Altering Stability and Activity of CYP2A6."Biochemical Biophysical Research Communications. (In press). (2001)

[Publications] Takeshi Ozeki et al.: "Cooperative regulation of the transcription of human dihydrodiol dehydrogenase (DD) 4/AKR1C4 gene by hepatocyte neclear factor (HNF) -4α/γ and HNF-1α."Biochemical Journal. (In press). (2001)

[Publications] Noritaka Ariyoshi et al.: "Pharmacogenetics on cancer chemotherapy : from basic studies."Japanese Journal of Clinical Pharmacology and Therapeutics. (In press). (2001)

[Publications] Taisei Mushiroda et al.: "Accumulation of the 1-methyl-4-phenylpyridinium ion (MPP+) in suncus (Suncus murinus) brain : Implication for flavin-containing monooxygenase activity in brain microvessels."Chemical Research in Toxicology. (In press). (2001)

[Publications] Loriot, M-A et al.: "Genetic polymorphism of cytochrome P450 2A6 in a case control study on lung cancer in a French population."Pharmacogenetics. 11. 39-44 (2001)

[Publications] Noritaka Ariyoshi et al.: "Studies on the genetic polymorphism of CYP2A6."Drug Metabolism and Disposition. 15. 57-61 (2000)

[Publications] Hirotaka Kushida et al.: "Development of a Salmonella tester strain sensitive to promutagenic N-nitrosamines : expression of recombinant CYP2A6 and human NADPH-cytochrome P450 reductase in S.typhimurium YG7108."Mutation Research. 471. 135-143 (2000)

[Publications] Noritaka Ariyoshi et al.: "Structural characterization of a new variant of the CYP2A6 gene (CYP2A6*1B) apparently diagnosed as heterozygotes of CYP2A6*1A and CYP2A6*4C."Pharmacogenetics. 10. 678-693 (2000)

[Publications] Taisei Mushiroda et al.: "The house musk shrew (Suncus murinus) : a unique animal with extremely low level of expression of mRNA for CYP3A and flavin-containing monooxygenase."Comparative Biochemistry & Physiology. 126. 225-234 (2000)

[Publications] Hirotaka Kushida et al.: "Metabolic activation of N-alkylnitrosamines in genetically engineered Salmonella typhimurium expressing CYP2E1 or CYP2A6 together with human NADPH-cytochrome P450 reductase."Carcinogenesis. 21. 1227-1232 (2000)

[Publications] Eri Inoue et al.: "Development of bacterial expression system with high yield of CYP3A7, a human fetus-specific form of Cytochrome P450."Biochemical Biophysical Research Communications. 269. 623-627 (2000)

[Publications] Taisei Mushiroda et al.: "A high level expression of CYP2A in the lung of the Suncus (Suncus murinus) and its role in the Activation of 4- (methylntirosamino) -1- (3-pyridyl) -1-butanone (NNK)."Biochemical Biophysical Research Communications. 269. 393-396 (2000)

[Publications] Ken-ichi Fujita et al.: "Establishment of Salmonella strain expressing catalytically active human UDP-glucuronosyltransferase 1A1 (UGT1A1)."Life Science. 66. 1955-1967 (2000)

[Publications] Noritaka Ariyoshi et al.: "Handbook of Experimental Pharmacology"Springer-VerlagBerlin. (2001)

[Publications] 有吉範高: "月刊薬事2001年臨時増刊号"じほう. (2001)

[Publications] 鎌滝哲也: "薬物療法学"南江堂. (2001)

[Publications] 有吉範高: "月刊薬事3月臨時増刊号"じほう. 834 (2000)

[Publications] 鎌滝哲也: "薬物代謝学"東京化学同人. 282 (2000)

有吉範高北海道大学, 大学院・薬学研究科, 助教授 (00243957)

[Publications] Noritaka Ariyoshi et al.: "Structural characterization of a new variant of the CYP2A6 gene (CYP2A61B) apparently diagnosed as heterozygotes of CYP2A61A and CYP2A6*4C."Pharmacogenetics. 10. 678-693 (2000)