Cytochrome P450-mediated liver toxicity possibly via increasing sensitivity toward glycation products

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K15330
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Sojo University
• Principal Investigator: Miyauchi Yuu 崇城大学, 薬学部, 講師 (50799947)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: シトクロムP450 / 活性酸素種 / 糖化産物 / 肝障害

Outline of Final Research Achievements

Cytochrome P450 (CYP) is a key enzyme involved in drug/xenobiotic metabolism but is also predicted to trigger liver toxicity although its detailed mechanism remains unclear. In this study, I hypothesized that CYP increases sensitivity against glycation products, which results in hepatic toxicity. As a model of CYP-induced cells, I generated CYP3A4-introduced stable cells based on COS-1 cells. Sensitivity against glycation products will tested with this stable expression system in future studies. Further, I studied the toxicity of one of the glycation products, dihydropyrazine (DHP-3) by comparing it with other major glycation products, carboxymethyl-lysine and acrylamide. It was revealed that DHP-3 produced more reactive oxygen species than the other glycation products, which resulted in marked cytotoxicity.

Free Research Field

衛生薬学、薬物代謝、毒性学

Academic Significance and Societal Importance of the Research Achievements

特定の医薬品や環境汚染物質に曝露することで、肝臓におけるCYPの量は著しく増加する。CYPによる肝障害惹起のメカニズムとしては、副反応の産物である活性酸素種が着目されがちだが、アスコルビン酸のような抗酸化物質の併用だけでは肝障害を十分に予防することができないため、別の因子の寄与が予想される。本研究で着目した糖化産物は、食事により日常的に体内に取り込まれており、糖化産物に対する感受性の上昇はCYPによる肝障害惹起における新たなファクターとして期待される。