Biomarkers for the Assessment of Acetaminophen Induced Liver Injury

General, Applied and Systems Toxicology Pub Date : 2011-09-15 DOI:10.1002/9780470744307.GAT219

W. Pathmasiri, R. Snyder, J. Burgess, J. Popp, T. Fennell, S. Sumner

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引用次数: 2

Abstract

This chapter summarizes a selection of literature regarding the development of biomarkers of acetaminophen (APAP)–induced liver injury (AILI), and provides new data related to the use of metabolomics for the development of a noninvasive marker profile for AILI. Our research investigation used male rats dosed daily with APAP at 0, 10, or 1500 per kg per day for up to 9 days. Urine, blood, and liver were obtained following a day and nine. Metabolomics of urine and extracts of liver showed separation of groups based on dose and duration of dose. Serum transaminases were evaluated. Histopathological analysis revealed complex pathological incidences for three lobes of the liver (left, right, and median), where centrilobular hypertrophy, centrilobular necrosis, and centrilobular inflammation were prominent in all lobes. Subsets of metabolites were identified that correlated with presence of AILI, even in cases were clinically relevant serum enzymes were not consistently correlated with pathology findings. Metabolite changes consistent with the presence of liver damage correlated with interruptions in amino acid, histidine, purine and pyrimidine, and glutamate metabolism. This study reveals markers that could find pre-clinical and clinical use, and provides insights into mechanisms involved in AILI. Keywords: acetaminophen; APAP; liver injury; NMR; metabolomics

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评价对乙酰氨基酚所致肝损伤的生物标志物

本章总结了有关对乙酰氨基酚(APAP)诱导的肝损伤(AILI)生物标志物开发的文献，并提供了与使用代谢组学开发AILI无创标志物谱相关的新数据。我们的研究调查使用雄性大鼠，每天以每公斤0、10或1500的剂量给药APAP，持续9天。1天和9天后取尿液、血液和肝脏。尿液和肝脏提取物的代谢组学显示根据剂量和剂量持续时间分组。测定血清转氨酶。组织病理学分析显示肝三叶(左、右、正中)病变复杂，所有叶均表现为小叶中心肥大、小叶中心坏死和小叶中心炎症。发现代谢物亚群与AILI的存在相关，即使在临床相关的病例中，血清酶与病理结果并不一致。代谢物变化与肝损害的存在一致，与氨基酸、组氨酸、嘌呤、嘧啶和谷氨酸代谢中断相关。本研究揭示了可用于临床前和临床的标志物，并为了解AILI的机制提供了见解。关键词:对乙酰氨基酚;APAP即;肝损伤;核磁共振;代谢组学

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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General, Applied and Systems Toxicology

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