医学
胰腺炎
天冬酰胺酶
不利影响
维生素
急性胰腺炎
不良事件报告系统
棕榈酸视黄酯
相伴的
内科学
队列
药品
药理学
视黄醇
胃肠病学
白血病
淋巴细胞白血病
作者
Cheng‐Yu Tsai,Toshie Saito,Mayur Sarangdhar,Maisam Abu‐El‐Haija,Li Wen,Bomi Lee,Mang Yu,Den A. Lipata,Murli Manohar,Monique T. Barakat,Kévin Contrepois,Thai Hoa Tran,Yves Théorêt,Na Bo,Ying Ding,Kristen E. Stevenson,Elena J. Ladas,Lewis B. Silverman,Loredana Quadro,Tracy G. Anthony,Anil G. Jegga,Sohail Z. Husain
出处
期刊:Science Translational Medicine
[American Association for the Advancement of Science (AAAS)]
日期:2023-03-15
卷期号:15 (687)
被引量:1
标识
DOI:10.1126/scitranslmed.abn2110
摘要
Among drug-induced adverse events, pancreatitis is life-threatening and results in substantial morbidity. A prototype example is the pancreatitis caused by asparaginase, a crucial drug used to treat acute lymphoblastic leukemia (ALL). Here, we used a systems approach to identify the factors affecting asparaginase-associated pancreatitis (AAP). Connectivity Map analysis of the transcriptomic data showed that asparaginase-induced gene signatures were potentially reversed by retinoids (vitamin A and its analogs). Analysis of a large electronic health record database (TriNetX) and the U.S. Federal Drug Administration Adverse Events Reporting System demonstrated a reduction in AAP risk with concomitant exposure to vitamin A. Furthermore, we performed a global metabolomic screening of plasma samples from 24 individuals with ALL who developed pancreatitis (cases) and 26 individuals with ALL who did not develop pancreatitis (controls), before and after a single exposure to asparaginase. Screening from this discovery cohort revealed that plasma carotenoids were lower in the cases than in controls. This finding was validated in a larger external cohort. A 30-day dietary recall showed that the cases received less dietary vitamin A than the controls did. In mice, asparaginase administration alone was sufficient to reduce circulating and hepatic retinol. Based on these data, we propose that circulating retinoids protect against pancreatic inflammation and that asparaginase reduces circulating retinoids. Moreover, we show that AAP is more likely to develop with reduced dietary vitamin A intake. The systems approach taken for AAP provides an impetus to examine the role of dietary vitamin A supplementation in preventing or treating AAP.
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