JP5930170B2 - シトクロムp450酵素代謝活性パターンによる化合物の毒性予測法 - Google Patents
シトクロムp450酵素代謝活性パターンによる化合物の毒性予測法 Download PDFInfo
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- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Description
1)P450は、化合物へと一原子酸素を付加する反応を触媒する。この際生じた代謝物は、極性を増すことにより水溶性を獲得し、尿等を経て速やかに体内から排出される。一方、酸化反応で生じたエポキシ体等は、アルキル化などによりDNAと直接反応することにより変異原性または発ガン性を示す(非特許文献1)。
2)ヒトのP450遺伝子は57種あることが明らかになっている。とりわけ、これらのなかでも11種の薬物代謝型P450が外来性異物(外来性化合物)の代謝に重要であると考えられており、実際90%以上の化合物の代謝に関与しているとの推測もある。
項1.化合物の代謝に関与する複数のシトクロムP450による前記化合物の代謝パターンを解析し、該解析結果に基づき化合物の毒性を予測する方法。
項2.毒性が変異原性である、項1に記載の方法
項3.シトクロムP450がヒト由来である、項1又は2に記載の方法。
項4.代謝パターンを解析するためのP450が、シトクロムP450が、CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2J2, CYP2R1, CYP2W1, CYP3A4, CYP3A5, CYP4F2, CYP4F12, CYP4X1, CYP17A1, CYP27A1, CYP51A1からなる群から選ばれる複数のP450である、項1〜3のいずれかに記載に方法。
項5.前記化合物が薬物または食品成分である項1〜4のいずれかに記載の方法。
項6.化合物の代謝に関与する複数のシトクロムP450が酸素センサーと積層固定されたバイオチップである項1〜5のいずれかに記載の方法。
(i) P450は化合物へと一原子酸素を添加する反応を触媒する。この反応は、いわゆる酵素反応でいう鍵と鍵穴の関係でもあることから、酸素添加の起こりやすい部位は化合物とP450酵素の関係のみで一義的に決定され、他の生体成分(例えば他の酵素や核酸、蛋白質等)は関係しない。
(ii) P450反応パターンは化合物の毒性と1対1の関係にある。
シトクロムP450(P450、CYP)は、農薬、医薬品などを含む種々の生体外異物の解毒的代謝や代謝的活性化などに関与しており、化合物の毒性を評価する上で、P450による代謝反応を明らかにすることは重要である。これまで肝細胞や膜画分に含まれるP450分子を用いた代謝活性のインビトロアッセイ手法が多く開発されてきた。本発明者らは、ルテニウム錯体を含んだ酸素センサー層(シリカ)と担持マトリックスに固定化されたシトクロムP450を積層化し、多様なP450分子種の酵素反応を、溶存酸素濃度変化として高効率にアッセイする技術を確立した(図1)。図1の基板の詳細は、特許文献2に記載されている。このようなP450/アガロース層とを担持した基板を用いることで、P450分子種によらず代謝活性を取得することが可能になった。化合物に対するP450分子種の活性は、化合物の構造や特性に依存した特異的なものである。従って、P450分子種を並列に配置したチップによって得られる代謝パターンを、その化合物の毒性(変異原性)を示す指標として用いられるのではないかというアイデアを得た。
Claims (5)
- 化合物の代謝に関与する12種から23種のシトクロムP450による前記化合物の代謝パターンを解析し、当該結果に基づき化合物の変異原性を予測する方法。
- シトクロムP450がヒト由来である、請求項1に記載の方法。
- 代謝パターンを解析するためのシトクロムP450が、CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2J2, CYP2R1, CYP2W1, CYP3A4, CYP3A5, CYP4F2, CYP4F12, CYP4X1, CYP17A1, CYP27A1, CYP51A1からなる群から選ばれる12種から23種のP450である、請求項1又は2に記載に方法。
- 前記化合物が薬物または食品成分である請求項1〜3のいずれかに記載の方法。
- 化合物の代謝に関与する12種から23種のシトクロムP450が酸素センサーと積層固定されたバイオチップである請求項1〜4のいずれかに記載の方法。
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