Centre for Pharmacology and Toxicology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany.
The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, Box 12137, Durham, NC 27709, USA.
Genome Med. 2013 Sep 27;5(9):86. doi: 10.1186/gm493. eCollection 2013.
Acetaminophen (APAP) is a commonly used analgesic. However, its use is associated with drug-induced liver injury (DILI). It is a prominent cause of acute liver failure, with APAP hepatotoxicity far exceeding other causes of acute liver failure in the United States. In order to improve its safe use this study aimed to identify individuals at risk for DILI prior to drug treatment by searching for non-genetic serum markers in healthy subjects susceptible to APAP-induced liver injury (AILI).
Healthy volunteers (n = 36) received either placebo or acetaminophen at the maximum daily dose of 4 g for 7 days. Blood samples were taken prior to and after APAP treatment. Serum proteomic profiling was done by 2D SDS-PAGE and matrix-assisted laser desorption/ionization-time of flight-mass spectrometry. Additionally, the proteins C-reactive protein, haptoglobin and hemopexin were studied by quantitative immunoassays.
One-third of study subjects presented more than four-fold increased alanine transaminase activity to evidence liver injury, while serum proteomics informed on 20 proteins as significantly regulated. These function primarily in acute phase and immune response. Pre-treatment associations included C-reactive protein, haptoglobin isoforms and retinol binding protein being up to six-fold higher in AILI susceptible individuals, whereas alpha1-antitrypsin, serum amyloid A, kininogen and transtyretin were regulated by nearly five-fold in AILI responders. When compared with published findings for steatohepatitis and cases of hepatocellular, cholestatic and mixed DILI, 10 proteins were identified as uniquely associated with risk for AILI, including plasminogen. Notably, this zymogen facilitates macrophage chemotactic migration and inflammatory response as reported for plasminogen-deficient mice shown to be resistant to APAP hepatotoxicity. Finally, analysis of a publicly available database of gene expression profiles of cultures of human hepatocytes treated with drugs labeled as no- (n = 8), low- (n = 45) or most-DILI-concern (n = 39) confirmed regulation of the identified biomarkers to demonstrate utility in predicting risk for liver injury.
The significant regulation of acute phase reactants points to an important link between AILI and the immune system. Monitoring of serum acute phase reactants prior to drug treatment may contribute to prevention and management of AILI, and may also be of utility for other drugs with known liver liabilities.
对乙酰氨基酚（APAP）是一种常用的镇痛药。然而，它的使用与药物引起的肝损伤（DILI）有关。它是急性肝衰竭的一个主要原因，在美国，APAP 肝毒性远远超过其他原因引起的急性肝衰竭。为了提高其安全使用，本研究旨在通过寻找对乙酰氨基酚诱导的肝损伤（AILI）易感的健康受试者中的非遗传血清标志物，在药物治疗前识别发生 DILI 的风险个体。
健康志愿者（n=36）接受安慰剂或最大日剂量 4 g 的对乙酰氨基酚治疗 7 天。在接受 APAP 治疗前后采集血样。通过二维 SDS-PAGE 和基质辅助激光解吸/电离飞行时间质谱进行血清蛋白质组学分析。此外，通过定量免疫测定法研究 C 反应蛋白、触珠蛋白和血红素结合蛋白。
三分之一的研究对象的丙氨酸转氨酶活性增加了四倍以上，表明有肝损伤，而血清蛋白质组学则显示有 20 种蛋白质显著调节。这些蛋白质主要参与急性期和免疫反应。在易感个体中，C 反应蛋白、触珠蛋白同工型和视黄醇结合蛋白的预处理相关性高达 6 倍，而α1-抗胰蛋白酶、血清淀粉样 A、激肽原和转铁蛋白在 AILI 反应者中调节近 5 倍。与发表的关于脂肪性肝炎和肝细胞性、胆汁淤积性和混合性 DILI 的研究结果相比，10 种蛋白质被鉴定为与 AILI 风险独特相关，包括纤溶酶原。值得注意的是，这种酶原促进巨噬细胞趋化迁移和炎症反应，正如报道的纤溶酶原缺陷小鼠对 APAP 肝毒性有抵抗力。最后，分析了一个公开的人类肝细胞药物治疗基因表达谱数据库，这些药物被标记为无（n=8）、低（n=45）或最关注 DILI（n=39），结果证实了所鉴定的生物标志物的调节，证明了其在预测肝损伤风险方面的应用。
急性期反应物的显著调节表明 AILI 与免疫系统之间存在重要联系。在药物治疗前监测血清急性期反应物可能有助于预防和管理 AILI，也可能对其他已知有肝脏风险的药物有用。
