Keio University · 화학
오에 토모요끼 교수의 연구실은 간 대사 효소인 사이트로크롬 P450에 의한 약물의 생체활성 대사 반응, 특히 페놀 유도체의 쿠이놀 생성 반응과 관련된 새로운 대사 경로를 중심으로 연구를 진행하고 있습니다. 특히, 페놀 화합물이 사이트로크롬 P450에 의해 산화되어 히드로퀴논 또는 쿠이놀로 전환되는 메커니즘과 그 반응 메커니즘에서 산소 원자의 기여를 규명하고 있으며, 이는 약물의 간 독성 예측 및 생체활성 대사체 분석에 기여합니다. 또한, 반응성 대사체를 추적하고 평가하는 방식의 새로운 분석 기법 개발을 통해 약물의 간 손상 잠재성 평가에 기여하고 있습니다.
표시된 성과는 수집된 데이터 기준으로 산출되며, 일부 차이가 있을 수 있습니다.
When various p-substituted phenols (substituent = NO2, CN, CH2OH, COCH3, COPh, COOH, F, Cl, and Br) were incubated with rat liver microsomes, the substituent was eliminated to produce hydroquinone, and the reaction was inhibited by CO and a cytochrome P450-specific inhibitor. In the case of p-cresol (substituent = CH3), p-toluquinol was formed instead of hydroquinone. Experiments using 18O2 proved that the elimination is accompanied with ipso-substitution by the oxygen atom of the active species
We have already reported that the quinol formation from some para-alkylphenols, which is a novel metabolic pathway catalyzed by cytochrome P-450, occurs in a rat liver microsomal system (). In the present study, we investigated whether estrone and 17beta-estadiol, each of which contains a p-alkylphenol moiety, are also oxidized into the corresponding quinols by cytochrome P-450. Six recombinant human cytochrome P-450 enzymes, CYP1A1, CYP1A2, CYP2B6, CYP2C9, CYP2E1, and CYP3A4, were tested. The r
A trapping approach for semi-quantitative assessment of bioactivation potential has been established for new chemical entities by using [(35)S]cysteine and [(14)C]sodium cyanide as trapping reagents. Reactive metabolites were trapped as radioactive adducts with the trapping reagents to be analyzed by radio-LC(/MS). As a reference, hepatotoxic drugs (clozapine, diclofenac, R-(+)-pulegone and troglitazone) were tested in the [(35)S]cysteine trapping assay and the proposed structures of the cystein
Diclofenac (DCF) is widely used as a nonsteroidal anti-inflammatory drug; however, it is associated with severe liver injury. This adverse reaction is thought to be related to the reactive quinone imine (QI) and acyl glucuronide (AG) metabolites of DCF, but it remains controversial which reactive metabolites mainly contribute to DCF-induced toxicity. In this study, we synthesized five types of DCF analogs that were designed to mitigate the formation of reactive QI and/or AG metabolites and evalu
