環境変異原の生体円代謝と複合作用

• Project/Area Number: 01602036
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Research Institution: The University of Tokushima
• Principal Investigator: 大西 克成 徳島大学, 医学部, 教授 (10037400)
• Co-Investigator(Kenkyū-buntansha): 山添 康 慶応義塾大学, 医学部, 講師 (00112699) ; 長尾 美奈子 国立がんセンター研究所, 発がん研究部, 部長 (40100151) ; 早津 彦哉 岡山大学, 薬学部, 教授 (10012593) ; 渡部 烈 東京薬科大学, 薬学部, 教授 (00057316) ; 辰巳 淳 広島大学, 医学部, 教授 (90037581)
• Project Period (FY): 1987 – 1989
• Project Status: Completed (Fiscal Year 1989)
• Budget Amount: ¥13,700,000 (Direct Cost: ¥13,700,000); Fiscal Year 1989: ¥13,700,000 (Direct Cost: ¥13,700,000)
• Keywords: 環境変異原 / 代謝活性化 / 腸肝循環 / 複合作用 / 抱合体 / ヘテロサイクリックアミン / アレーン / クロロフィル

Research Abstract

1.哺乳動物個体の突然変異の検出系を開発するために、ラムダファージ/supFトランスジェニックマウスを作成した。2.環境変異原の生体内代謝(1)タバコ煙中に含まれる5ーメチルクリセン(5-MCR)の活性化体である5-MCRサルフェートの生成は、カニクイザル肺では他の動物より高く、不活性化酵素であるグルタチオン(GSH)トランスフェラーゼの活性は低かった。(2)1-nitropyrene(1-NP)の酸化的代謝産物である1-NP oxidesはGSH抱合体として胆汁中に排泄され、小腸内でシステイン(Cys)抱合体にまで分解され、さらに盲腸・大腸内容物特に嫌気性菌のCys抱合体β-lyaseによって分解された。これらのoxdesのGSH抱合体は代謝されて腸管から再吸収されたが、この腸肝循環に腸内菌が関与していた。(3)水産用医薬品であるβ-(5-nitro-2ーfuryl)-p-carboxystyreneの動物での代謝産物として6物質を同定し、これらの代謝に関与する酵素を明らかにした。3.環境変異原の人体汚染評価としてアフラトキシンB_1(AFB_1)を取り上げ、AFB_1-DNA付加体を調べた。日本の肝がん患者では17人中14人にこの付加体が認められた。その量は、腫瘍部位で0.9-2.3ng/mg DNA、非腫瘍部位で0.8-4.0ng/mg DNAであった。4.変異原の複合作用と修飾 (1)コーヒーの水可溶性高分子物質中の二価以上のフェノール類が、空気中の酸素によってキノン類に変化し、ヘテロサイクリックアミン(HA)のアミノ基を修飾して変異原性を低下させた。(2)クロロフィルとクロロフィリンはHAの変異原性並びにDNA傷害作用を抑制した。クロロフィリン結合セフアロース(Ch-Seph)はTrp化合物を吸着し、ChーSephとTrpーPー2とを同時にハエに与えるとTrpーPー2の活性が抑えられた。(3)N-ヒドロキシアミンの肝スルフォトランスフェラーゼによる活性化は、この酵素の生合成を介して視床下部-下垂体-性腺系によって調節されていることを明らかにした。

Research Products

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