Pattern Recognition Analysis for Hepatotoxicity Induced by Acetaminophen Using Plasma and Urinary 1H NMR-Based Metabolomics in Humans
Pattern Recognition Analysis for Hepatotoxicity Induced by Acetaminophen Using Plasma and Urinary 1H NMR-Based Metabolomics in Humans
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DOI：
10.1021/ac402390q
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发表时间：
2013-12-03
影响因子：
7.4
通讯作者：
Kim, Kyu-Bong
中科院分区：
文献类型：
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作者：
Kim, Ji Won;Ryu, Sung Ha;Kim, Kyu-Bong
药物性肝损伤（DILI）目前是一个日益相关的健康问题。然而，现有的生物标志物不能可靠地检测或量化DILL风险。因此，本研究的目的是使用代谢组学方法和质子核磁共振（NMR）平台比较评价从接受对乙酰氨基酚（APAP）治疗的人中获得的血浆和尿液生物标志物。将APAP（3g/天，每8小时两片500 mg片剂）给予20名健康韩国男性（年龄，20-29岁）7天。在给药前和给药期间以及末次给药后6天每天采集尿液。采用主成分分析（PCA）和偏最小二乘判别分析对这些尿样的NMR谱进行了分析。虽然天冬氨酸转氨酶和乳酸脱氢酶的活性显着增加后7天的APAP治疗，血清生化指标的天冬氨酸转氨酶，丙氨酸转氨酶，碱性磷酸酶，总胆红素，γ-谷氨酰转肽酶，乳酸脱氢酶在正常范围内的肝功能。然而，尿液和血浆H-1 NMR光谱显示APAP治疗前和治疗后通过PCA进行全局代谢组学分析的不同聚类。尿中内源性代谢产物三甲胺-N-氧化物、柠檬酸盐、3-氯酪氨酸、苯丙氨酸、甘氨酸、马尿酸盐和戊二酸盐以及血浆内源性代谢产物（如乳酸盐、葡萄糖、3-羟基异戊酸盐、异亮氨酸、乙酰甘氨酸、丙酮、乙酸盐、谷氨酰胺、乙醇和异丁酸盐）对人体APAP给药有显著反应。尿液和血浆内源性代谢物比血清生化参数更敏感。这些结果可能适用于预测或筛选潜在的肝毒性引起的其他药物使用尿液和血浆的H-1 NMR分析。
Drug-induced liver injury (DILI) is currently an increasingly relevant health issue. However, available biomarkers do not reliably detect or quantify DILL risk. Therefore, the purpose of this study was to comparatively evaluate plasma and urinary biomarkers obtained from humans treated with acetaminophen (APAP) using a metabolomics approach and a proton nuclear magnetic resonance (NMR) platform. APAP (3 g/day, two 500 mg tablets every 8 h) was administered to 20 healthy Korean males (age, 20-29 years) for 7 days. Urine was collected daily before and during dosing and 6 days after the final dose. NMR spectra of these urine samples were analyzed using principal component analysis (PCA) and partial least-squares-discrimination analysis. Although the activities of aspartate aminotransferase and lactate dehydrogenase were significantly increased 7 days post-APAP treatment, serum biochemical parameters of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, gamma-glutamyl transpeptidase, and lactate dehydrogenase were within normal range of hepatic function. However, urine and plasma H-1 NMR spectroscopy revealed different clustering between predosing and after APAP treatment for global metabolomic profiling through PCA. Urinary endogenous metabolites of trimethylamine-N-oxide, citrate, 3-chlorotyrosine, phenylalanine, glycine, hippurate, and glutarate as well as plasma endogenous metabolites such as lactate, glucose, 3-hydroxyisovalerate, isoleucine, acetylglycine, acetone, acetate, glutamine, ethanol, and isobutyrate responded significantly to APAP dosing in humans. Urinary and plasma endogenous metabolites were more sensitive than serum biochemical parameters. These results might be applied to predict or screen potential hepatotoxicity caused by other drugs using urinary and plasma H-1 NMR analyses.