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）是当今世界上最常见的药物，用于治疗疼痛和发烧，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的特征，并涉及父型药物的生物转化与化学反应性代谢物N-乙酰基-P-苯甲酰酮亚胺（NAPQI），该亚胺（NAPQI）与细胞蛋白共价结合。通过与肝谷胱甘肽（GSH）上的胱烷基硫醇结合来解毒。在有毒的APAP暴露中，GSH储量会耗尽，增加了与细胞蛋白上结合与胱烷基硫醇结合的NAPQI的量，从而产生了多种APAP蛋白质加合物。该提案的主要位点率先测量了总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过量的儿童和成人中测试了该生物标志物，与APAP相关的急性急性肝失效，以及最近接受APAP剂量剂量的患者。在接受推荐剂量APAP的成年人中，发现了低水平的APAP添加剂，并发现了这些患者的APAP加合物水平较高和升高的转氨酶值升高的关联。根据我们最近的数据，将测试以下假设：在接触APAP暴露的儿童和青少年中，（1）在接受治疗性暴露的住院儿童中，将发现APAP添加剂，（2）存在独特的和特定的APAP内收蛋白，并且与APAP暴露量的幅度相差（3）唯一的AP和POTERIAP的功能将差异化。使用最先进的，以加合物为中心的蛋白质组学方法，以下建议将识别并评估接受APAP毒性的特定“第二代”生物标志物在接受治疗剂量APAP的儿童/青少年以及接受过量APAP的儿童/青少年中。参加儿科药理学研究单位网络（PPRU；国家儿童健康与人类发展研究所）的儿科学术中心将有助于临床样本收集以及分析和药代动力学数据分析。相对于新描述的APAP毒性的代谢组标记和肝毒性指标的新代谢组标记，鉴定了特定的APAP蛋白加合物和这些特定加合物的检查将为改善儿童和青少年APAP风险和安全性的评估奠定基础。公共卫生相关性：对乙酰氨基酚是当今世界上最常用的药物用于治疗疼痛和发烧。当使用非常大剂量的对乙酰氨基酚或发生有毒的过量药物时，会导致严重的肝损伤。对乙酰氨基酚的推荐剂量最近被证明在某些患者中会导致轻度肝损伤。先前的研究表明，对乙酰氨基酚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的肝损伤的标志物。该建议将使用先进的蛋白质鉴定方法来识别对乙酰氨基酚改变的确切蛋白质。研究样本将从接受推荐剂量的对乙酰氨基酚的儿童和青少年以及乙酰氨基酚过量的受害者的儿童和青少年获得。将对这些样品进行复杂的蛋白质鉴定研究，并将研究与常见的肝损伤临床测试有关。这些新知识将增加我们对对乙酰氨基酚如何导致肝损伤的理解，以及某些患者可能面临更大的肝损伤风险。