Identification of new mechanistic biomarkers of adverse responses to acetaminophe

对乙酰氨基酚不良反应的新机制生物标志物的鉴定

• 批准号: 8063985
• 负责人: Laura P James
• 金额: $ 37.41万
• 依托单位: ARKANSAS CHILDREN'S HOSPITAL RES INST
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8063985
• 关键词: Acetaminophen; Acetylcysteine; Acute; Acute Liver Failure; Address; Adolescent; Adult; Antidotes; Binding; Biological Assay; Biological Markers; Categories; Characteristics; Child; Child health care; Childhood; Citric Acid Cycle; Clinical; Clinical Markers; Data; Data Analyses; Detection; Development; Dose; Drug Kinetics; Drug usage; Evaluation; Exposure to; Fever; Foundations; Future; Generations; Glutathione; Health; Hepatic; Hepatotoxicity; High Pressure Liquid Chromatography; Hospitalized Child; Human Development; Imines; Immune Sera; Injury; Institutes; Knowledge; Lead; Liver; Mass Spectrum Analysis; Measurement; Measures; Metabolic Biotransformation; Methods; Molecular; Nomograms; One-Step dentin bonding system; Overdose; Oxidation-Reduction; Pain; Parents; Patients; Pharmaceutical Preparations; Population; Populations at Risk; Proteins; Proteomics; Rattus; Relative (related person); Research; Risk; Risk Assessment; Role; Safety; Sampling; Sampling Studies; Site; Specificity; Staging; Sulfhydryl Compounds; Terminology; Testing; Therapeutic; Time; To specify; Toxic effect; Toxicant exposure; Toxicity Tests; Transaminases; United States; Work; acetaminophen overdose; adduct; base; improved; indexing; metabolomics; p-Benzoquinones; para-benzoquinone; pediatric pharmacology; peripheral blood; response; sample collection

DESCRIPTION (provided by applicant): Acetaminophen (APAP) is the most common drug used for the treatment of pain and fever in the world today and is also the leading cause of acute liver failure in the United States. The initial stages of APAP toxicity have been well-characterized and involve the biotransformation of the parent drug to a chemically reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI), which binds covalently to cellular proteins. NAPQI is detoxified by binding to the cysteinyl thiol on hepatic glutathione (GSH). In toxic APAP exposures, GSH reserves are depleted, increasing the amount of NAPQI that binds to cysteinyl thiols on cellular proteins, producing a variety of APAP-protein adducts. The lead site for this proposal pioneered the measurement of total APAP-protein adducts (APAP-ADDUCTS) as clinical markers of APAP toxicity and tested this biomarker in children and adults with acute APAP overdose, APAP-related acute liver failure, and recently, in patients receiving recommended doses of APAP. In adults receiving recommended doses of APAP, low levels of APAP-ADDUCTS were detected and an association was found for higher APAP- ADDUCT levels and higher elevated transaminase values levels in these patients. Based on our recent data, the following hypotheses will be tested: In children and adolescents with APAP exposures, (1) APAP-ADDUCTS will be detected in hospitalized children receiving therapeutic exposures, (2) unique and specific APAP adduct proteins exist and differ as a function of the magnitude of APAP exposure and, (3) unique protein adducts will correspond with established measures and co- variates of APAP toxicity. Using state-of-the-art, adduct-focused proteomic approaches, the following proposal will identify and evaluate examine specific "second generation" biomarkers of APAP toxicity in children/adolescents receiving therapeutic doses of APAP and in children/adolescents that have received overdoses of APAP. Pediatric academic centers participating in the Network of Pediatric Pharmacology Research Units (PPRU; National Institutes of Child Health and Human Development) will assist with clinical sample collection and analytical and pharmacokinetic data analysis. Identification of specific APAP protein adducts and examination of these specific adducts relative to newly described metabolomic markers of APAP toxicity and established indices of liver toxicity will lay the foundation for improved future assessments of risk and safety for APAP in children and adolescents. PUBLIC HEALTH RELEVANCE: Acetaminophen is the most common drug used in the world today for the treatment of pain and fever. When very large doses of acetaminophen are used or when a toxic overdose occurs, severe liver injury results. Acetaminophen, at recommended doses, has recently been shown to cause mild liver injury in some patients. Previous studies have shown that proteins in the liver are changed by acetaminophen and these protein changes can serve as markers of liver injury from acetaminophen. This proposal will use advanced protein identification methods to identify the exact proteins that are changed by acetaminophen. Study samples will be obtained from children and adolescents that are receiving recommended doses of acetaminophen and from children and adolescents that are victims of acetaminophen overdoses. Sophisticated protein identification studies will be performed on these samples and this information will be studied in relationship to common clinical tests for liver injury. This new knowledge will increase our understanding of how acetaminophen may cause liver injury and how some patients may be at greater risk for liver injury.

描述（由申请人提供）：对乙酰氨基酚（APAP）是当今世界上最常用的用于治疗疼痛和发烧的药物，也是美国急性肝衰竭的主要原因。 APAP 毒性的初始阶段已得到充分表征，涉及母体药物生物转化为化学反应性代谢物 N-乙酰基-对苯醌亚胺 (NAPQI)，该代谢物与细胞蛋白质共价结合。 NAPQI 通过与肝谷胱甘肽 (GSH) 上的半胱氨酰硫醇结合而解毒。在有毒的 APAP 暴露中，GSH 储备被耗尽，增加了与细胞蛋白上的半胱氨酰硫醇结合的 NAPQI 的量，产生各种 APAP 蛋白加合物。该提案的主导站点率先测量了总 APAP 蛋白加合物 (APAP-ADDUCTS) 作为 APAP 毒性的临床标志物，并在患有急性 APAP 过量、APAP 相关急性肝衰竭的儿童和成人中测试了该生物标志物，最近，在接受推荐剂量的 APAP 的患者。在接受推荐剂量的 APAP 的成人中，检测到低水平的 APAP-ADDUCT，并且发现这些患者中较高的 APAP-ADDUCT 水平和较高的转氨酶值水平存在关联。根据我们最近的数据，将测试以下假设：在接受 APAP 暴露的儿童和青少年中，(1) 在接受治疗暴露的住院儿童中将检测到 APAP-ADDUCTS，(2) 存在独特且特定的 APAP 加合物蛋白，并且与以下情况不同： APAP 暴露程度的函数，(3) 独特的蛋白质加合物将与 APAP 毒性的既定测量和协变量相对应。使用最先进的、以加合物为重点的蛋白质组学方法，以下提案将识别和评估检查接受治疗剂量的 APAP 的儿童/青少年和接受过量药物的儿童/青少年的 APAP 毒性的特定“第二代”生物标志物的APAP。参与儿科药理学研究单位网络（PPRU；美国国立儿童健康和人类发展研究所）的儿科学术中心将协助临床样本收集以及分析和药代动力学数据分析。特定 APAP 蛋白加合物的鉴定以及这些特定加合物相对于新描述的 APAP 毒性代谢组学标记物和已建立的肝毒性指数的检查将为改进未来儿童和青少年 APAP 风险和安全性评估奠定基础。公共卫生相关性：对乙酰氨基酚是当今世界上最常用的治疗疼痛和发烧的药物。当使用大剂量的对乙酰氨基酚或发生中毒过量时，会导致严重的肝损伤。最近显示，推荐剂量的对乙酰氨基酚会导致一些患者出现轻度肝损伤。先前的研究表明，对乙酰氨基酚会改变肝脏中的蛋白质，这些蛋白质变化可以作为对乙酰氨基酚造成的肝损伤的标志。该提案将使用先进的蛋白质鉴定方法来鉴定被对乙酰氨基酚改变的确切蛋白质。研究样本将从正在接受推荐剂量的对乙酰氨基酚的儿童和青少年以及对乙酰氨基酚过量的儿童和青少年中获取。将对这些样本进行复杂的蛋白质鉴定研究，并将根据肝损伤的常见临床测试来研究这些信息。这一新知识将加深我们对对乙酰氨基酚如何导致肝损伤以及某些患者如何面临更大肝损伤风险的理解。