1999 Fiscal Year Annual Research Report

タイ人に見られる魚臭症候群の原因となる遺伝子の解析

Research Project

Project/Area Number	10044224
Research Institution	HOKKAIDO UNIVERSITY
Principal Investigator	鎌滝哲也北海道大学, 大学院・薬学研究科, 教授 (00009177)
Co-Investigator(Kenkyū-buntansha)	有吉範高北海道大学, 大学院・薬学研究科, 助教授 (00243957) 高橋芳樹北海道大学, 大学院・薬学研究科, 助手 (80292019) 中山佳都夫北海道大学, 大学院・薬学研究科, 助手 (20261323) 藤田健一北海道大学, 大学院・薬学研究科, 助手 (60281820)
Keywords	トリメチルアミン / FMO / 遺伝的多型 / 遺伝病 / 遺伝子治療 / 異種細胞発現系 / ヒトゲノム / 遺伝子解析
Research Abstract	魚臭症候群の原因を解明することを目的とし、体臭症状を訴える魚臭症候群の疑いのあるタイ人の尿サンプルを解析した。魚臭症候群と疑われるタイ人12名の尿中トリメチルアミンN-酸化体排泄率を測定した結果、どの検体も体臭症状を訴えていないタイ人の値と同程度であった。したがって、ヘテロ接合体で魚臭症候群の原因となる変異を遺伝子上に有している可能性が考えられたので、トリメチルアミンの代謝に最も寄与しているフラビン含有モノオキシゲナーゼ(FMO)3の遺伝子の塩基配列を解析した。解析した検体のうち2名のFMO3遺伝子のエクソン3においてGからAへの変異(アミノ酸置換V58l)が見出された。この変異は現在までに報告されていない新規変異であった。この遺伝子変異がこの疾患の原因となっている可能性が考えられたので、この変異を有する変異型FMO3をサルモネラ菌に発現させ、野生型FMO3の酵素活性と比較した。メチマゾールおよびチオベンズアミドS-酸化酸素活性が野生型FMO3に比べて、それぞれ約25%、約40%に低下した。また、魚臭症候群の原因物質であるトリメチルアミンのN-酸化酵素活性は野生型FMO3の約20%に低下した。したがって、この変異はFMO3の酵素活性を低下させる変異であることが明らかとなった。解析した2検体はこの変異をヘテロ接合体で有しているため、食事による負荷がかかったときにトリメチルアミンからN-酸化体への代謝が十分に行われず魚臭症候群様の症状が現れると考えられる。

Research Products
(20 results)

All Other

All Publications (20 results)

[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. (in press).
[Publications] Yasumasa Sasaki, et al.: "Cooperative regulation of CYP2C12 gene expression by signal transducer and activator of transcription 5 (STAT5) and liver-specific factor in female rats"Journal of Biological Chemistry. 274. 37117-37124 (1999)
[Publications] Tomonori Tateishi, et al.: "Analysis of the CYP2D6 gene in relation to dextromethorphan O-demethylation capaciy in Japanese population"Clinical Pharmacology and Therapeutics. 65. 570-575 (1999)
[Publications] Miki Nakajima, et al.: "Genetic polymorphism in the 5"-flanking region of human CYP1A2 gene : effect on the CYP1A2 inducibility in humans"Journal of Biochemistry. 125. 803-808 (1999)
[Publications] Ken-ichi Nunoya, et al.: "CYP2A6 gene deletion responsible for the in vivo polymorphic metabolism of (+)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidine-4-one hydrochloride in humans"Journal of Pharmacology and Experimental Therapeutics. 289. 437-442 (1999)
[Publications] Michihiro Chida, et al.: "A new variant CYP2D6 allele (CYP2D6^★21) with a single insertion in exon 5 in a Japanese population associated with a poor matabolizer phenotype"Pharmacogenetics. 9. 287-293 (1999)
[Publications] Taisei Mushiroda, et al.: "The Suncus (Suncus murlnus) shows poor metabolic phenotype for trimethylamine N-oxygenation"Toxicology and Applied Pharmacology. In press.
[Publications] Toshiyuki Kume, et al.: "Characterization of a novel varitant (S145C/L311V) of 3-hydroxysteroid/dihydrodiol dehydrogenase in human liver"Pharmacogenetics. 9. 763-771 (1999)
[Publications] Masami Miyamoto, et al.: "CYP2A6 gene deletion reduces susceptibiliy to lung cancer"Biochemical Biophysical Research Communications. 261. 658-660 (1999)
[Publications] Michihiro Chida, et al.: "Genetic polymorphism of CYP2D6 in Japanese population"Pharmacogenetics. 9. 601-605 (1999)
[Publications] Ken-ichi Nunoya, et al.: "Homologous unequal cross-over within the human CYP2A gene cluster as a mechanism for the deletion of entire CYP2A6 gene associated with the poor"Journal of Biochemistry. 126. 402-407 (1999)
[Publications] Taisei Mushiroda, et al.: "Sensitive assay of trimethylamine N-oxide in liver microsomes by head-space gas chromatography with flame thermionic detection"Journal of Chromatography. 734. 319-323 (1999)
[Publications] Michihiro Chida, et al.: "Detection of three genetic polymorphisms in the 5'-flanking region and the intron 1 of human CYP1A2 in the Japanese population"Japanese Journal of Cancer Research. 90. 899-902 (1999)
[Publications] Timothy Marcylo, et al.: "Protection against the bacterial mutagenicity of heterocyclic amines by purpurin, a natural anthraquinone pigment"Mutation Research. 444. 451-461 (1999)
[Publications] Taisei Mushiroda, et al.: "The Suncus (Suncus murinus) shows poor metabolic phenotype for trimethylamine N-oxygenation"Toxicology and Applied Pharmacology. (in press).
[Publications] Erin Schuetz, et al.: "The glucocorticoid receptor is essential for induction of cytochrome P4502B by steroids but not for drug or steroid induction of CYP3A or P450 reductase"Drug Metabolism and Disposition. (in press).
[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-"Biochemical Biophysical Research Communications. (in press).
[Publications] 鎌滝哲也: "薬物療法学"南山堂(In prees).
[Publications] 有吉範高: "別冊医学のあゆみ消化器疾患"医歯薬出版株式会社. 562 (1999)
[Publications] 中山佳都夫: "別冊医学のあゆみ消化器疾患"医歯薬出版株式会社. 562 (1999)

1999 Fiscal Year Annual Research Report

タイ人に見られる魚臭症候群の原因となる遺伝子の解析

Principal Investigator

鎌滝 哲也 北海道大学, 大学院・薬学研究科, 教授 (00009177)

Research Products

[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. (in press).

[Publications] Yasumasa Sasaki, et al.: "Cooperative regulation of CYP2C12 gene expression by signal transducer and activator of transcription 5 (STAT5) and liver-specific factor in female rats"Journal of Biological Chemistry. 274. 37117-37124 (1999)

[Publications] Tomonori Tateishi, et al.: "Analysis of the CYP2D6 gene in relation to dextromethorphan O-demethylation capaciy in Japanese population"Clinical Pharmacology and Therapeutics. 65. 570-575 (1999)

[Publications] Miki Nakajima, et al.: "Genetic polymorphism in the 5"-flanking region of human CYP1A2 gene : effect on the CYP1A2 inducibility in humans"Journal of Biochemistry. 125. 803-808 (1999)

[Publications] Ken-ichi Nunoya, et al.: "CYP2A6 gene deletion responsible for the in vivo polymorphic metabolism of (+)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidine-4-one hydrochloride in humans"Journal of Pharmacology and Experimental Therapeutics. 289. 437-442 (1999)

[Publications] Michihiro Chida, et al.: "A new variant CYP2D6 allele (CYP2D6^★21) with a single insertion in exon 5 in a Japanese population associated with a poor matabolizer phenotype"Pharmacogenetics. 9. 287-293 (1999)

[Publications] Taisei Mushiroda, et al.: "The Suncus (Suncus murlnus) shows poor metabolic phenotype for trimethylamine N-oxygenation"Toxicology and Applied Pharmacology. In press.

[Publications] Toshiyuki Kume, et al.: "Characterization of a novel varitant (S145C/L311V) of 3-hydroxysteroid/dihydrodiol dehydrogenase in human liver"Pharmacogenetics. 9. 763-771 (1999)

[Publications] Masami Miyamoto, et al.: "CYP2A6 gene deletion reduces susceptibiliy to lung cancer"Biochemical Biophysical Research Communications. 261. 658-660 (1999)

[Publications] Michihiro Chida, et al.: "Genetic polymorphism of CYP2D6 in Japanese population"Pharmacogenetics. 9. 601-605 (1999)

[Publications] Ken-ichi Nunoya, et al.: "Homologous unequal cross-over within the human CYP2A gene cluster as a mechanism for the deletion of entire CYP2A6 gene associated with the poor"Journal of Biochemistry. 126. 402-407 (1999)

[Publications] Taisei Mushiroda, et al.: "Sensitive assay of trimethylamine N-oxide in liver microsomes by head-space gas chromatography with flame thermionic detection"Journal of Chromatography. 734. 319-323 (1999)

[Publications] Michihiro Chida, et al.: "Detection of three genetic polymorphisms in the 5'-flanking region and the intron 1 of human CYP1A2 in the Japanese population"Japanese Journal of Cancer Research. 90. 899-902 (1999)

[Publications] Timothy Marcylo, et al.: "Protection against the bacterial mutagenicity of heterocyclic amines by purpurin, a natural anthraquinone pigment"Mutation Research. 444. 451-461 (1999)

[Publications] Taisei Mushiroda, et al.: "The Suncus (Suncus murinus) shows poor metabolic phenotype for trimethylamine N-oxygenation"Toxicology and Applied Pharmacology. (in press).

[Publications] Erin Schuetz, et al.: "The glucocorticoid receptor is essential for induction of cytochrome P4502B by steroids but not for drug or steroid induction of CYP3A or P450 reductase"Drug Metabolism and Disposition. (in press).

[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-"Biochemical Biophysical Research Communications. (in press).

[Publications] 鎌滝哲也: "薬物療法学"南山堂(In prees).

[Publications] 有吉範高: "別冊 医学のあゆみ 消化器疾患"医歯薬出版株式会社. 562 (1999)

[Publications] 中山佳都夫: "別冊 医学のあゆみ 消化器疾患"医歯薬出版株式会社. 562 (1999)

鎌滝哲也北海道大学, 大学院・薬学研究科, 教授 (00009177)

[Publications] 有吉範高: "別冊医学のあゆみ消化器疾患"医歯薬出版株式会社. 562 (1999)

[Publications] 中山佳都夫: "別冊医学のあゆみ消化器疾患"医歯薬出版株式会社. 562 (1999)