Elucidation of reductases related with side effects of clinical drugs

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K08367
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Kanazawa University
• Principal Investigator: Fukami Tatsuki 金沢大学, 薬学系, 准教授 (00532300)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 薬物代謝反応 / 還元反応 / 医薬品毒性 / ニトロ基含有酵素 / Non-P450

Outline of Final Research Achievements

Enzyme responsible for reduction of nitrazepam, which causes hepatotoxicity as a side effect, was purified from human liver, resulting in the isolation of aldehyde oxidase 1 (AOX1). Nitrazepam reductase activity was enhanced in the presence of N-methylnicotinamide, which is an endogenous substrate of AOX1. In the process of reduction, nitrazepam was converted to N-hydroxyl amine form, which has been accepted to related with several toxicity because of its instability. This unstable intermediate may cause hepatotoxicity by nitrazepam. It was investigated which compounds were reduced by AOX1 in human, resulting that some compounds reported to cause hepatotoxicity as a side effect, including dantrolene and flutamide, were reduced by AOX1. Common characteristics among them were to possess relatively electron-deficient nitro group.

Free Research Field

薬物代謝

Academic Significance and Societal Importance of the Research Achievements

医薬品開発において、薬物動態の理解が進んでいるため薬物間相互作用が原因となり候補化合物がドロップアウトする例は減少したものの、医薬品毒性に関しては情報不足の点からドロップアウトの原因として未だ横ばいである。本検討では、副作用発症メカニズムを明らかにする目的でニトロ基還元反応に注目し、医薬品のニトロ基還元酵素としてアルデヒドオキシダーゼ(AOX1)を単離、同定した。また、AOX1による還元体が副作用発現に関与することも示唆された。どのような化学構造のニトロ基含有医薬品がAOX1により還元されるか明らかにした点から、創薬において副作用を回避するための有用な情報を提供できたものと考えられる。