Elucidation and prevention of the mechanism of hepatic sinusoidal obstruction syndrome (SOS) induced by DNA alkylating agents

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K15255
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Kagoshima University
• Principal Investigator: Miyahara Emiko 鹿児島大学, 医歯学総合研究科, 客員研究員 (20778427)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Keywords: D N Aアルキル化剤 / シクロフォスファミド / ブスルファン / 肝類洞閉塞症候群（SOS）

Outline of Final Research Achievements

C57BL/6J mice whose ALDH1 gene expression was suppressed by siRNA were treated with CY. After the treatment, the liver tissue was observed by electron microscopy. Small lipid droplets containing lamellar bodies were observed in liver parenchymal cells, atrophy of interlobular bile ducts, and fat droplets containing lamellar bodies in sinusoidal wall cells.
Since accumulation of the lamellar bodies was observed after CY administration, Di-docosahexaenoyl (C22:6)-bis(monoacylglycerol)phosphate (BMP), a biomarker for drug-induced dyslipidemia (PL) was measured by liquid chromatography-mass spectrometer. PL is a phospholipid storage disorder characterized by the accumulation of lamellar bodies in the liver. BMP measurements showed no significant differences between the CY-treated and non-treated groups, suggesting that the phospholipids produced by CY are different from the usual typical PL.

Free Research Field

毒性学

Academic Significance and Societal Importance of the Research Achievements

DNAアルキル化剤大量投与後に発症する肝類洞閉塞症候群（SOS）は、発症及び経過の予測が難しい。SOS発症には個人差があり、それはDNAアルキル化剤から生じる様々な代謝物の産生や除去に関与する因子に由来することが予測される。これらの因子を明らかにすることはSOSの発症予測や予防、重症化予防に役立つ。Busulfan (BU)やcyclophosphamide (CY)など大量のDNAアルキル化剤を用いた造血幹細胞移植においてBUやCYは同じ効果を有する代替薬のない抗がん剤として使用され続けているため社会的意義は大きいと考えられる。