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1The Need for Biomarkers in Dia1.IntroductionLiver injury due to both prescription and over-the-counter drugs is a growing public health problem.Although drug-induced liver injury(DILI)is a rare cause of acute liver injury in clinical practice,it is the leading cause of acute liver failure(ALF)in the US and most of Europe.处方药和非处方药导致的肝损伤是一个日益严重的公共卫生问题。尽管药物诱导的肝损伤（DILI）在临床实践中是急性肝损伤的罕见原因，但它是美国和大多数欧洲的急性肝衰竭（ALF）的主要原因2.1.IntroductionLiver injury du1.IntroductionDespite the extensive safety tests performed in the process of getting a drug to market,DILI remains enigmatic and cannot be predicted in preclinical and clinical trials.Even though different genetic variants and biomarkers have been associated with the risk of developing DILI,hepatotoxicity remains a very common side effect.尽管在药物上市的过程中进行了广泛的安全性测试，但肝损伤仍然是神秘的，并且不能在临床前和临床试验中预测。不同的遗传变异体和生物标志物与肝损伤发展的风险相关，肝毒性仍然是非常常见的副作用。3.1.IntroductionDespite the ex1.IntroductionIn this review we will focus on the potential role ofmetabolomic study on the diagnosis and prognosis of DILI.在这篇综述中，我们将重点关注代谢组学在肝损伤的诊断和预断中的潜在作用。4.1.IntroductionIn this review2.The Main Challenges in DILI:Accuracy of Diagnosis and Prediction of EvolutionCurrently,DILI is diagnosed by exclusion of other liver diseases and is frequently misdiagnosed.An important part in the diagnosis of DILI is to establish a temporal association between a drug and the onset of liver damage.However,in many cases,setting a causal link can be a complex task as most of the idiosyncratic drug-induced reactions occur roughly between a range of 1-2 weeks and 2-3 months from the onset of drug administration 目前，肝损伤是通过排除其他肝病进行诊断的，而且经常被误诊。DILI诊断的一个重要部分是建立药物与肝损伤起始之间的时间关联。然而，在许多情况下，设置因果关联可以说是一件复杂的任务，因为大多数特异性药物诱导的反应大致在给药开始的1-2周和2-3个月的范围内才发生5.2.The Main Challenges in DILI2.The Main Challenges in DILI:Accuracy of Diagnosis and Prediction of EvolutionImportantly,our knowledge is scarce not only in terms of diagnostic accuracy.The natural history of DILI is still not completely understood重要的是，我们的知识不仅在准确诊断性方面知道的很少。而且肝损伤的自然史仍然没有完全理解6.2.The Main Challenges in DILI2.The Main Challenges in DILI:Accuracy of Diagnosis and Prediction of Evolutionmetabolomics is emerging forcefully in order to identify early toxicity biomarkers from biofluids collected through minimally invasive procedures that are specific indicators of liver damage.代谢组学可以通过作为肝损伤的具体指标的微创手术收集生物流体来识别早期毒性的生物标志物。7.2.The Main Challenges in DILI3.Metabolomics:Concept and DefinitionMetabolomics offers a view distinct from Genomics and Proteomics.While Genomics and Proteomics tell us what“can happen,”metabolomics tells us what is“really happening”and,therefore,is the science that can better characterize the phenotypes of living organisms.代谢组学提供了不同于基因组学和蛋白质组学的一种全新视图。基因组学和蛋白质组学告诉我们“可能发生”，但代谢组学告诉我们“真正发生发生了什么”，因此是更好地表征活性生物体表型的科学8.3.Metabolomics:Concept and D3.Metabolomics:Concept and DefinitionThe main analytical methods used in metabolomic analyses are nuclear magnetic resonance(NMR)and mass spectrometry(MS).代谢组学分析中使用的主要分析方法是核磁共振（NMR）和质谱（MS）。9.3.Metabolomics:Concept and D4.The Potential Role of Metabolic Profiling inthe Diagnosis and Prognosis of DILIBiomarkers are analyzed from blood,urine,or other biological samples that may provide insight into the severity,cause,or outcome of an injury to a specific tissue来自于血液，尿液或其他生物样品中的生物标志物，可以洞察肝损伤的特定组织的的严重性，原因或结果。10.4.The Potential Role of Metab4.The Potential Role of Metabolic Profiling inthe Diagnosis and Prognosis of DILIWinnike analyzed the metabolomic profiles in urine samples from 58 healthy adults before and after receiving 4g of APAP per day for 7 days(a regimen that produces mild liver injury in about one-third of subjects).Urine metabolomic profile obtained 2 days prior to treatment were not sufficient to predict the development of mild liver damage,but the profiles obtained after a short period of administration of APAP were able to predict it.Winnike分析了来自每天给予4gAPAP持续7天（在约三分之一的受试者中产生轻度肝损伤的方案）58名健康成人的尿液样品中的代谢组学概况。在治疗前2天获得的尿液代谢组学概况不足以预测肝损伤的发展，但在短时间施用APAP后获得的概况能够预测11.4.The Potential Role of Metab4.The Potential Role of Metabolic Profiling inthe Diagnosis and Prognosis of DILIHuo and collaborators have published a study in humans,using a metabolomic approach to identify diagnostic biomarkers of DILI They evaluated the liver toxicity of sodium valproate using ultra-performance LC-MS and HNMR-based metabolomics analysis of serum samples from 34 epileptic patients receiving this drugHUO和合作者在人中进行了一项研究，他们使用代谢组学方法来鉴定诊断DILI的生物标志物，使用超高效液相色谱-质谱和基于HNMR的代谢组学分析评估了接受丙戊酸钠这种药物的34例癫痫患者的血清样品中的肝毒性，12.4.The Potential Role of Metab4.The Potential Role of Metabolic Profiling inthe Diagnosis and Prognosis of DILIThey found differences in metabolites involved in glycolysis,lipid metabolism,energy metabolism,and amino acids metabolism between patients with normal liver function and those with elevated liver enzymes due to the mentioned drug.Thus,they could define metabolites associated with valproate sodium-induced hepatotoxicity.This work demonstrates the potentia lof using metabolomics to discover biomarkers of hepatotoxicity.他们发现正常肝功能的患者和由于使用丙戊酸钠后肝酶升高的患者中的，糖酵解，脂质代谢，能量代谢和氨基酸代谢中的代谢物的差异。因此，他们可以锁定丙戊酸钠诱导肝毒性相关的代谢物。这项工作表明使用代谢组学可以发现肝毒性的生物标志物13.4.The Potential Role of Metab5.ConclusionsIn this sense,the tremendous growth metabolomics has experienced over the last decade is notable,with remarkable applications in the area of liver toxicity.It is in this field where metabolomics has shown the potential of combining physiological and metabolic pathway information to drug toxicity studies.在过去的十年中，代谢组学在肝脏毒性领域的应用得到了显著的和快速的发展，正是在这个领域，代谢组学已经显示出将生理和代谢途径信息与药物毒性研究相结合的潜力。14.5.ConclusionsIn this sense,t5.ConclusionsMoreover,its ability to rapidly detect many metabolites using NMR and MS from biofluid obtained by minimally invasive techniques makes metabolomics a promising tool in the discovery of biomarkers allocated to establish an early diagnosis and prognosis of DILI.此外，通过微创技术获得的生物流体，借助NMR和MS可以被快速检测，在早起诊断和预断肝损伤中的生物标志物，代谢组学是一个非常具有前景的工具。15.5.ConclusionsMoreover,its abi thanks16.thanks16.
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