- 學位論文
探討引起G6PD溶血性貧血的藥物之交互作用網路
Investigating interaction networks for drug-induced glucose-6-phosphate dehydrogenase deficiency-related hemolysis
摘要
G6PD缺乏症是一種的性聯遺傳的先天疾病。患者因在日常生活中接觸某些食品 (如：蠶豆)、化學物質和部分藥物後，而出現急性溶血性貧血症狀。然而，已知有些藥物對G6PD缺乏患者會導致溶血，目前卻沒有標準方法可以測試該藥物的風險危害。 本研究共分析42種高風險、36種低風險和53種安全的藥物，利用ChemDIS系統找出高風險、低風險和安全藥物的交互作用網路，並找出重要生物標記。研究發現有風險藥物與人體蛋白質G6PD交互作用具有一致性，其他KMO、MHD2和NF-kB1也是關鍵蛋白質。而Beclin1和Diablo和細胞凋亡有關，是影響高風險藥物引起溶血的重要因素之一。由基因本體分析發現高風險藥物產生干擾素和宿主遭受到感染反應時相似；主要代謝路徑是經由清道夫接受器的結合和吸收配體產生作用。 以交互作用的蛋白質交互作用進行風險預測，發現高風險藥物精確度可達56%以上，有風險藥物精確度更可達80%以上；不論是高風險藥物或是有風險藥物，在保持一定精確度之下同時加入Beclin1和Diablo做預測，兩者的敏感度可提高至40 %以上，未來可做為藥物上市前的風險評估測試。
並列摘要
Glucose 6-phosphate dehydrogenase deficiency, an X-linked disorder, is the most common enzymatic disorder of red blood cells in humans. It can cause hemolysis after exposure to drugs with a high redox potential, fava beans, selected infections, or metabolic abnormalities. Several drugs have been found to be high risk of hemolytic anemia for G6PD deficiency patients. However, there is no standard method to evaluate drugs for their risks of hemolytic anemia. We propose to utilize ChemDIS system to study the interaction network of drugs and proteins and identify important biomarkers capable of predict corresponding risks. A total of 42 high-risk drugs, 36 low-risk drugs and 53 safe drugs were collected. Several proteins have been identified as important biomarkers such as G6PD, KMO, MHD2 and NF-kB1. The interaction networks of high-risk, low-risk and safe drugs were analyzed to find out the important biomarkers. This study identified G6PD, KMO, MHD2 and NF-kB1 as key biomarkers. Beclin1 and Diablo associated with apoptosis are also useful biomarkers that could be important factors for hemolysis of high-risk drugs. For the risk prediction of drugs using the identified biomarkers, this study found that the precision for high-risk drugs is 56%, the precision for risk drugs is over 80%. When Beclin1 and Diablo are combined for prediction, sensitivity can be improved to higher than 40%. The prediction methods could be used to screen drug hemolytic risk.