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  • Original Article
  • OPEN ACCESS

MicroRNAs in Drug-induced Liver Injury

  • Li-Min Li,
  • Dong Wang and
  • Ke Zen*
 Author information
Journal of Clinical and Translational Hepatology 2014;2(3):162-169

DOI: 10.14218/JCTH.2014.00015

Abstract

Drug-induced liver injury (DILI) is a leading cause of acute liver failure, and a major reason for the recall of marketed drugs. Detection of potential liver injury is a challenge for clinical management and preclinical drug safety studies, as well as a great obstacle to the development of new, effective and safe drugs. Currently, serum levels of alanine and aspartate aminotransferases are the gold standard for evaluating liver injury. However, these levels are assessed by nonspecific, insensitive, and non-predictive tests, and often result in false-positive results. Therefore, there is an urgent need for better DILI biomarkers to guide risk assessment and patient management. The discovery of microRNAs (miRNAs) as a new class of gene expression regulators has triggered an explosion of research, particularly on the measurement of miRNAs in various body fluids as biomarkers for many human diseases. The properties of miRNA-based biomarkers, such as tissue specificity and high stability and sensitivity, suggest they could be used as novel, minimally invasive and stable DILI biomarkers. In the current review, we summarize recent progress concerning the role of miRNAs in diagnosing and monitoring both clinical and preclinical DILI, and discuss the main advantages and challenges of miRNAs as novel DILI biomarkers.

Keywords

Biomarker, Diagnosis, Drug-induced liver injury (DILI), MicroRNA

Introduction

Drug-induced liver injury (DILI) is a growing challenge because of the increasing number of drugs used in medical care, and the increasing number of individuals who take them.1,2 A database (www.livertox.nih.gov ) has been established to provide up-to-date, comprehensive clinical information on DILI for both the general physician and the specialist. A recent epidemiologic study by Bjornsson and co-workers suggested that approximately 20 new cases of DILI per 100,000 persons occur each year.2 DILI is also one of the most frequent causes for the termination of drug development or withdrawal of approved drugs, and therefore, has an enormous economic impact on health care expenditures.3–6 Moreover, it is the leading cause of acute liver failure.7 Of the estimated 10000 documented drugs developed for humans, more than 1000 have been associated with DILI.8 The main causes of DILI in the United States are antibiotics, agents for the central nervous system, health foods and dietary supplements.4,9,10 In China, traditional Chinese medicine and anti-tuberculosis drugs are the major causes of DILI.4,11,12 Children, women, and the elderly are more vulnerable to DILI, and the susceptibility is related to genetic and environmental factors.13–15 Although there are many consistent features of DILI, early diagnosis is still challenging due to the lack of specific and sensitive clinical features.8,16

Classification of DILI

DILI is usually categorized as non-idiosyncratic (predictable) and idiosyncratic (unpredictable).17–19 The most common example of non-idiosyncratic DILI is from acetaminophen, which is one of the most commonly used medicines with a very high safety profile when used properly.20,21 However, if misused, either intentionally or accidentally, significant liver injury can occur,22 which has a short latency period, and is dose-related. This hepatotoxicity can also be studied in animal models.23–26 Although idiosyncratic DILI has a longer/variable latency and is less common, it comprises the majority of clinical DILI cases.27–29 Idiosyncratic DILI generally cannot be recapitulated in traditional animal models or in clinical trials.28,30–32 Examples of this kind of DILI include those related to amoxicillin/clavulanate, non-steroidal anti-inflammatory drugs, and isoniazid.13,33,34

Pathogenesis and treatment of DILI

The bulk of drug metabolism occurs in the liver, which is also vulnerable to damage from drug metabolites. The more common idiosyncratic type of DILI has no significant relationship with drug or dose,27–29 and the mechanism can be divided into allergic35 and metabolic idiosyncratic.36 The allergic form is closely related to the high variability of the human leukocyte antigen system on chromosome 6,37–39 whereas the metabolic form is closely associated with the genetic polymorphisms of individual drug-metabolizing enzymes, such as cytochrome P450 enzymes,40 uridine diphosphate glucuronosyltransferase,41 and N-acetyltransferase.42 In addition, oxidative stress and the host inflammatory response also play important roles in the development of idiosyncratic DILI. There is mixed evidence to support the role of host factors such as age, sex, obesity,43,44 and chronic liver disease in the development of DILI, and genetic predisposition appears to be a risk factor for injury from specific drugs.38

Treatment for most forms of DILI is focused on supportive care and requires longitudinal monitoring of the patient and laboratory work. Suspected cases of idiosyncratic DILI can be categorized as hepatitic, cholestatic, or mixed on the basis of the degree/ratio of abnormalities in the alanine aminotransferase (ALT) and alkaline phosphatase.45 However, a careful evaluation for other causes of liver disease should be performed, and sometimes, a liver biopsy is needed. The mainstay of treatment for DILI is the immediate discontinuation of the offending drugs, and avoidance of drugs with similar chemical structures or pharmacologic effects. The timing of discontinuation of hepatotoxic drugs is controversial. Some investigators believe that the elevation of liver enzymes, including aspartate aminotransferase (AST) or ALT > 3× upper limit of normal (ULN) or alkaline phosphatase > 1.5× ULN, accompanied by elevation of bilirubin levels (> 3× ULN), indicate serious liver damage, and should trigger immediate discontinuation of suspected causative drugs.46–49 The Federal Drug Administration has proposed the following criteria for immediate cessation of the drug in question: ALT > 8× ULN, ALT > 5× ULN for two weeks, ALT > 3× ULN accompanied by serum bilirubin > 2× ULN, pro-thrombin time-international normalized ratio > 1.5× ULN, or the appearance of liver damage symptoms. For oral agents, the severity of many cases of DILI can be decreased by reducing the residual drug in the gastrointestinal tract by means of gastric lavage, catharsis, and adsorption, or the use of diuresis, hemodialysis and other methods, within six hours of ingestion.50,51

Diagnosis of DILI

It is very important to have a reliable and predictable biomarker for DILI, and considerable effort has been made to identify markers specifically for early detection. The Federal Drug Administration recently endorsed four standard serum biomarkers, including ALT, AST, total bilirubin and alkaline phosphatase, to help identify severe DILI events in clinical trials.21,49,51 However, limitations of these current blood-based biomarkers include an unacceptable frequency of false positives/negatives, poor sensitivity, and lack of tissue specificity. For example, serum ALT activity is also associated with kidney damage and muscle necrosis.52–54 Liver damage is only considered when serum ALT levels reach two to four times that of the control group, thus the best treatment period can easily be missed.55 Fenofibrate can induce elevated serum transaminases, but does not cause significant liver damage, resulting in false positives.56,57 In addition, the markers may become elevated only after substantial and sometimes irreversible tissue damage.58 All of these characteristics decrease confidence in the utility of aminotransferases as biomarkers for DILI. Ideally, more sensitive and predictive biomarkers that respond very early before irreversible injury has occurred would offer improved outcomes.

MicroRNAs

MicroRNAs (miRNAs) are a recently discovered class of small, endogenous, non-coding, single-stranded RNAs that are 19–24 nucleotides in length.59 They are highly conserved, and regulate approximately 30% of all gene expression at a post-transcriptional level.59 miRNAs were first reported in 1993 in a study by Lee et al. who showed that Lin-4 controlled the timing of sexual development in Caenorhabditis elegans.60 To date, there are 24521 entries representing hairpin precursor miRNAs, which correspond to 30432 mature miRNAs expressed in 206 species (miRBase Release 20; http://www.mirbase.org ). The major function of miRNA is to modulate gene expression either by translational repression or mRNA degradation. Binding of a miRNA to the 3′-untranslated region of mRNA with partial complementarity, as occurs in animals,59,60 will inhibit translation, whereas perfect complementarity, such as occurs in plants,59,61 will specifically direct mRNA cleavage resulting in target gene degradation.

Similar to other molecules involved in regulating gene expression, the expression levels of miRNAs differ significantly in various tissues and at distinct developmental stages.59,61–63 The diversity of miRNA sequences, structures, abundance and expression make them powerful regulators of mRNA that are involved in development, proliferation, differentiation, apoptosis, energy metabolism and other physiologic processes.63 Therefore, alterations in miRNA expression may reflect a change in the physiologic and pathologic states. Fig. 1 shows the number of retrievable manuscripts over the past 12 years in PubMed using “microRNA” and “biomarkers” as the keywords. An impressive and increasing number of related studies were observed, showing that the use of miRNA as a biomarker is currently one of the most important topics in the field.

The number of articles listed on Pubmed concerning miRNAs as biomarkers published from 2002 to 2013
Fig. 1  The number of articles listed on Pubmed concerning miRNAs as biomarkers published from 2002 to 2013

Recent studies have shown that there are a large number of circulating miRNAs, and that altered miRNA expression profiles are closely related to disease. The discovery of miRNAs in circulating blood was first reported by Lawrie and co-workers in 2008.64 Subsequently, the presence of stable miRNAs in plasma and serum was reported by other researchers.65,66 Gilad and co-workers found that miRNA can be detected in serum, urine, saliva, and amniotic and other fluids, and placenta-associated serum miRNAs are significantly elevated during pregnancy.67 These studies demonstrated that miRNAs are present in bodily fluid of humans and other animals, such as mice, rats, bovine fetuses, calves and horses, which laid the foundation for the use of miRNAs as noninvasive biomarkers, and their application in cancer prevention and disease diagnosis.68–71

MicroRNA and pathogenesis of DILI

Responses to xenobiotics can be regulated or modulated by miRNAs in liver. For example, the exposure of rats to liver hepatotoxins, such as acetaminophen or carbon tetrachloride, results in altered expression of various miRNAs, including a decrease in miR-298 and miR-370, which are thought to regulate an oxidative stress-related gene.72 An increase in levels of several oncogenic miRNAs, such as the 17–92 cluster, miR-106a, and miR-34, was detected in rat livers following exposure to tamoxifen, a potent hepatocarcinogen.73 Another research group demonstrated that dioxins, which are ubiquitously present in the environment and tend to accumulate in humans and wildlife, alter the expression of miR-101a and its target, cyclooxygenase-2, which plays a significant role in liver damage.74 Using the same method, Endo et al. found that in patients with suppressed expression of miR-106b, the hepatotoxic drug halothane caused upregulation of signal transducer and activator of transcription 3, which was involved with the resultant severe liver injury.75 Furthermore, there are many studies reporting that drug-metabolizing enzymes, such as cytochrome P450 1B1, which is highly expressed in human liver, are targeted by certain miRNAs.76–78 Taken together, these studies demonstrate that miRNAs play a significant role in the pharmacologic and toxicologic progression of hepatotoxicity. As shown in Fig. 2, miRNAs may be involved in multiple DILI developmental processes via regulation of their target genes.

Pathways by which miRNAs may be involved in the development of drug-induced liver injury (DILI).
Fig. 2  Pathways by which miRNAs may be involved in the development of drug-induced liver injury (DILI).

Drugs induce hepatocyte injury through their toxic metabolites generated via CYP450. The toxic metabolites can induce the consumption of ATP, production of reactive oxygen species and formation of drug-protein/DNA complexes, which result in mitochondrial uncoupling and hepatocellular apoptosis. When there is no ATP consumption, the reactive metabolites increase the mitochondrial permeability, causing an increase in cytosolic Ca2+ and cell necrosis. All of these processes can affect the expression of miRNAs, and the deregulated miRNAs can, in turn, regulate the development of DILI through their target genes.

Circulating miRNAs as potential biomarkers of DILI

Although studies of miRNAs as biomarkers are primarily concentrated in cancer research,69,70 their potential as toxicologic biomarkers have also been recently explored.79 Over the past several years, many animal and clinical studies have been published showing that miRNAs have an advantage over the conventional biomarkers for DILI. They are exceptionally stable, can be highly liver-specific and remarkably altered in pathologic states, are readily detectable in easily accessible bodily fluids, and are strictly conserved among species. Table 1 summarizes the published reports using circulating miRNAs in the blood and urine as new DILI biomarkers.

Table 1

Circulating miRNAs in drug-induced liver injury (DILI)

Drug or chemicalSpeciesSample typeQuantification methodmiRNA expression in DILIClinical relevanceReference
Acetaminophen, CCl4RatLivermiRNA array, qPCRmiR-153↑, miR-302b↑, miR-337↑, miR-363↑, miR-409-5p↑, miR-542-3p↑, miR-29c↓, miR-298↓, miR-327↓, miR-342↓, miR-370↓, miR-376c↓, miR-494↓, miR-503↓Early diagnosis72
AcetaminophenMousePlasmamiRNA array, qPCRmiR-122↑, miR-192↑, miR-193↑, miR-710↓, miR-711↓, miR-483↓Early diagnosis80
D-GalN/LPS, alcoholMousePlasmaqPCRmiR-122↑Diagnosis and monitoring81
Acetaminophen, unidentified drugsHumanPlasmaqPCRmiR-122↑, miR-192↑Diagnosis and pharmaceutical evaluation92
Alcohol, CpG/LPS, acetaminophenMousePlasma, SerumqPCRmiR-122↑, miR-155↑, miR-146a↑Differentiate hepatocyte injury and inflammation82
Acetaminophen, ANIT, allyl alcohol, phenobarbital, doxorubicinRatPlasmaqPCRmiR-122↑Diagnosis and monitoring87
ParaquatHumanSerumqPCRmiR-122↑, miR-192↓, miR-483↓, miR-711↓Diagnosis96
AcetaminophenHumanWhole BloodmiRNA array, qPCRmiR-29c↑, miR-19a↑, miR-19b↑, miR-802↑, miR-374a↓, miR-505↓Diagnosis93
Acetaminophen, herb drugRatSerummiRNA array, qPCRmiR-122↑, miR-192↑, miR-193↑, miR-200a↑, miR-101a↑, miR-323↓, miR-322↓, miR-327↓, miR-380↓, miR-214↓, miR-342-3p↓Diagnosis86
AcetaminophenMousePlasmamiRNA array, qPCRmiR-574-5p↑, miR-135a*↑, miR-466g↑, miR-1196↑, miR-466f-3p↑, miR-877↑, miR-342-3p↓, miR-195↓, miR-375↓, miR-29c↓, miR-148a↓, miR-652↓Medication guidance83
Acetaminophen, ANIT, methapyrilene, CCl4RatPlasmamiRNA array, qPCRmiR-200a*↑, let-7c-1*↑, miR-503↑, miR-337-3p↑, miR-10b↑, miR-190↓, miR-743b↓, miR-449c↓, miR-410↓, miR-10b*↓Diagnosis of different types of liver injury85
Acetaminophen, CCl4, penicillinRatUrinemiRNA array, qPCRmiR-185↑, miR-296↑, miR-484↑, miR-434↑, miR-20b-3p↑, miR-330*↑, miR-433↑, miR-664↑, miR-291a-5p↑, miR34c*↑Diagnosis of different types of liver injury91

Abbreviations: ANIT, alpha-naphthyl isothiocyanate; CpG, cytidine-phosphate-guanosine; CCl4, carbon tetrachloride; D-GalN, d-galactosamine; LPS, lipopolysaccharide; qPCR, quantitative real-time polymerase chain reaction.

Serum or plasma miRNAs as biomarkers in experimental DILI

A pioneer study by Wang et al. examined miRNAs as novel biomarkers in a well-established mouse model of acetaminophen-induced liver injury.80 The authors demonstrated that the liver-enriched miR-122 and miR-192 were the top two miRNAs elevated in blood in a dose-and exposure time-dependent manner. The levels of these miRNAs preceded and paralleled serum ALT and AST levels and corresponding liver histopathology.

Several independent groups have provided additional data supporting the use of miRNAs as DILI biomarkers. In 2010, one group confirmed the time-dependent increase of plasma miR-122 levels in mice that correlated with liver histopathology induced by D-galactosamine and alcohol.81 They also confirmed that the changes of miR-122 were larger than and preceded the changes in ALT. Importantly, significant increases in miR-122 were detected before obvious histopathologic changes in the liver, suggesting that miR-122 could be used for diagnosing and monitoring disease at early stages. Bala and co-workers discovered that serum plasma miR-122 and miR-155 were predominantly associated with the exosome-rich fraction in alcoholic and inflammatory liver injuries, whereas in acetaminophen-induced liver injury, these miRNAs were present mainly in the soluble protein-rich fraction.82 These results suggest that circulating miRNAs may serve as biomarkers to differentiate between hepatocyte injury and inflammation, and the exosome- or protein-associated miRNAs may provide further specific mechanisms of liver pathology. The same group also compared 40 plasma miRNAs that were dysregulated with lethal or sub-lethal doses of acetaminophen, and found that miR-574-5p, miR-135a, miR-466g, miR-1196, miR-466f-3p and miR-877 were upregulated in the setting of lethal hepatotoxicity, while miR-342-3p, miR-195, miR-375, miR-29c, miR-148a and miR-652 were markedly downregulated.83 Thus, differential expression of miRNAs in human plasma may be useful to distinguish lethal and sub-lethal hepatotoxicity.

Compared with mice, the susceptibility to acetaminophen-induced liver injury is lower in rats.84 Using rat models created by the administration of chemical or special diets, Yamaura et al. examined the levels of the plasma miRNAs in acute liver injury (hepatocellular injury or cholestasis) and chronic liver injury (steatosis, steatohepatitis, and fibrosis).85 Their results showed that miR-122 levels increased more quickly and dramatically than levels of aminotransferases, reflecting the extent of hepatocellular injury. Importantly, their study also demonstrated that the expression profiles of plasma miRNAs differed according to the type of liver injury, suggesting that these miRNAs could be specific and sensitive biomarkers for various types of liver injury. Su et al. also reported that miR-122, miR-192 and miR-193 have the potential to serve as sensitive, specific and noninvasive biomarkers for the diagnosis of herb-induced liver damage.86 Furthermore, Starckx and co-workers demonstrated that the levels of miR-122 in rat plasma were significantly increased following administration of four well-characterized compounds associated with different types and mechanisms of liver toxicity: acetaminophen, allyl alcohol, alpha-naphthyl isothiocyanate, and phenobarbital.87 The response of miR-122 secretion by mouse liver cells paralleled that of other markers, and was consistent with liver injury as indicated by ALT/AST and histopathologic evaluation. The changes of plasma miR-122 were also detected significantly earlier than other conventional biomarkers, and exhibited a wide dynamic range. Taken together, all the above discoveries demonstrate that miR-122 has great potential to be used as a biomarker of liver injury and may provide added value for assessing liver toxicity in both preclinical studies and the development of new drugs.

Urinary miRNAs as noninvasive biomarkers in experimental DILI

The discovery of circulating miRNAs in the urine and other bodily fluids has created a new approach for the discovery of noninvasive biomarkers of organ injury.88 For example, urine-derived miRNAs could become useful biomarkers for kidney89 and bladder diseases,90 or even for DILI. In a rat DILI model, urinary levels of some miRNAs were elevated, likely released from the liver after injury.91 High-dose acetaminophen-treated rats showed elevations of serum ALT/AST, histologic signs of liver injury, and significant increases in urinary miRNAs levels. Although low-dose acetaminophen-treated rats did not show histologic signs of liver injury or changes in serum ALT/AST, urinary levels of nine miRNAs were substantially increased. Similarly, carbon tetrachloride also led to an increase in urinary levels of 28 miRNAs, among which ten overlapped with the 44 identified in the acetaminophen-induced model. Therefore, urinary miRNAs appear to be another form of noninvasive DILI biomarker and may be useful for the classification of hepatotoxins. However, further studies are needed to examine their organ-specificity in detecting DILI.

Circulating miRNAs as biomarkers in human DILI

A study examining human subjects who suffered DILI showed that the plasma levels of both miR-122 and miR-192 were substantially higher in patients who suffered acetaminophen-induced liver injury than in those who did not.92 Moreover, levels of the liver-enriched miR-122, but not miR-192, correlated with serum ALT levels, consistent with results from a previous study in a mouse model.80 Their findings also showed that the level of circulating miR-122 decreased to baseline much earlier than serum ALT did, suggesting that miR-122 has a shorter circulatory half-life. This work provided the first convincing evidence that circulating miRNAs could be used as a human DILI biomarker. Jetten et al. also demonstrated that miR-19b and miR-29c were upregulated in human blood cells after treatment with low-dose acetaminophen.93 However, the level of ALT was not altered. These results suggest that the expression profile of circulating miRNAs may be altered at a very early stage when liver damage is undetectable using conventional markers. Indeed, another study showed that miR-122, along with high mobility group box-1 and full-length and caspase-cleaved keratin-18, were more sensitive than ALT at identifying acetaminophen-induced acute liver injury.94 Thulin and colleagues also showed that serum keratin-18 and miR-122 levels were significantly increased at an earlier time point and to a greater extent than ALT in patients with DILI.95

Paraquat is one of the most common toxic herbicides, and is widely used around the world. By comparing paraquat-exposed human subjects with healthy donors, Dingand and co-workers found that the serum levels of miR-122 were strongly increased and correlated well with the status of liver function.96 This pattern was similar to that was seen in the mouse acetaminophen-induced liver injury model.80 However, miR-192, also identified in the mouse study, was unexpectedly decreased two-to-eight-fold in human hepatic samples.

Conclusions

The prediction, diagnosis and management of DILI are very complicated issues. The current biomarkers or approaches to assess DILI include biochemical markers such as aminotransferases, total bile acids, histopathology or ultrastructural pathology, active metabolites and immune-related markers. However, due to the poor sensitivity, stability or specificity, these conventional toxicologic biomarkers cannot provide accurate information for early evaluation of liver hepatotoxicity. The development of novel, reliable and informative biomarkers remains an important issue in clinical and preclinical settings. Liver-specific miR-122 has been shown to be involved in various processes of liver development, differentiation, metabolism and stress responses.97–99 Compared with the conventional hepatotoxic markers, circulating miR-122 can effectively and consistently distinguish intrahepatic from extrahepatic damage with higher sensitivity and specificity.92–96 Thus, miR-122 is expected to be a preclinical and clinical biomarker of DILI.

Although the use of circulating miRNA levels for early diagnosis of DILI shows promise, further study is required before it is used in clinical applications. The major issues to be addressed include: 1) lack of association between miRNAs and mechanistic information on DILI; 2) lack of drug-specific miRNAs to diagnose various types of DILI; 3) lack of larger sample sizes validating the assay; and 4) lack of conventional detection methods that can be carried out in routine clinical laboratories, including standardized detection systems, standard reference materials, and quality control materials.100,101 More studies are required to demonstrate the mechanisms underlying the phenotypes of DILI, including research and investigation on the alterations of miRNAs in liver tissues after treatments with various drugs representing a broad range of DILI types, combining miRNAs with other biomarkers, and multicenter collaborations.

In conclusion, the use of miRNAs, especially miR-122, as noninvasive biomarkers for DILI shows great potential, but is still in its infancy. More research on circulating miRNAs is needed to validate the use of miRNAs as novel biomarkers of DILI.

Abbreviations

ALT: 

alanine aminotransferase

AST: 

aspartate aminotransferase

DILI: 

Drug-induced liver injury

miRNAs: 

microRNAs

ULN: 

upper limit of normal

Declarations

Acknowledgement

This work was supported by grants from the National Basic Research Program of China (973 Program, 2012CB517603 and 2011CB504803), the National Natural Science Foundation of China (No.31301061), the Natural Science Foundation of Jiangsu Province (No. BK2011013, BK20130564), and the Specialized Research Fund for the Doctoral Program of Higher Education (20130091120037).

Conflict of interest

None

Authors’ contributions

Analyzing the data (LML, DW), drafting the manuscript (LML, KZ).

References

  1. Acikgoz A, Giri S, Bader A. Detection of nanolevel drug metabolites in an organotypic culture ofprimary human hepatocytes and porcine hepatocytes with special reference to a two-compartment model. Int J Nanomed 2012;7:5859-5872 View Article PubMed/NCBI
  2. Bjornsson E, Bergmann O, Bjornsson HK, Olafsson S. The frequency of drug-induced liver injury (DILI) among patients receiving potentially hepatotoxic drugs: a population based study. Hepatology 2012;56:594a-595a View Article PubMed/NCBI
  3. Idilman R, Bektas M, Cinar K, Toruner M, Cerit ET, Doganay B. The Characteristics and Clinical Outcome of Drug-induced Liver Injury A Single-center Experience. J Clin Gastroenterol 2010;44:E128-E132 View Article PubMed/NCBI
  4. Leise MD, Poterucha JJ, Talwalkar JA. Drug-Induced Liver Injury. Mayo Clin Proc 2014;89:95-106 View Article PubMed/NCBI
  5. Watkins PB. Drug safety sciences and the bottleneck in drug development. Clin Pharmacol Ther 2011;89:788-790 View Article PubMed/NCBI
  6. Chen MJ, Vijay V, Shi Q, Liu ZC, Fang H, Tong WD. FDA-approved drug labeling for the study of drug-induced liver injury. Drug Discov Today 2011;16:697-703 View Article PubMed/NCBI
  7. Reuben A, Koch DG, Lee WM, Grp ALFS. Drug-Induced Acute Liver Failure: Results of a U.S. Multicenter, Prospective Study. Hepatology 2010;52:2065-2076 View Article PubMed/NCBI
  8. Shi Q, Hong HX, Senior J, Tong W. Biomarkers for drug-induced liver injury. Expert Rev Gastroenterol Hepatol 2010;4:225-234 View Article PubMed/NCBI
  9. Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J. Causes, Clinical Features, and Outcomes From a Prospective Study of Drug-induced Liver Injury in the United States. Gastroenterology 2008;135:1924-1934 View Article PubMed/NCBI
  10. Grant LM, Rockey DC. Drug-induced liver injury. Curr Opin Gastroenterol 2012;28:198-202 View Article PubMed/NCBI
  11. Zhou Y, Yang L, Liao Z, He X, Zhou Y, Guo H. Epidemiology of drug-induced liver injury in China: a systematic analysis of the Chinese literature including 21,789 patients. Eur J Gastroenterol Hepatol 2013;25:825-829 View Article PubMed/NCBI
  12. Li LM, Chen L, Deng GH, Tan WT, Dan YJ, Wang RQ. SLCO1B1*15 haplotype is associated with rifampin-induced liver injury. Mol Med Rep 2012;6:75-82 View Article PubMed/NCBI
  13. Lucena MI, Molokhia M, Shen YF, Urban TJ, Aithal GP, Andrade RJ. Susceptibility to Amoxicillin-Clavulanate-Induced Liver Injury Is Influenced by Multiple HLA Class I and II Alleles. Gastroenterology 2011;141:338-347 View Article PubMed/NCBI
  14. Watkins PB, Seeff LB. Drug-induced liver injury: Summary of a single topic - Clinical research conference. Hepatology 2006;43:618-631 View Article PubMed/NCBI
  15. Zopf Y, Rabe C, Neubert A, Gassmann KG, Rascher W, Hahn EG. Women encounter ADRs more often than do men. Eur J Clin Pharmacol 2008;64:999-1004 View Article PubMed/NCBI
  16. Watkins PB. Idiosyncratic liver injury: Challenges and approaches. Toxicol Pathol 2005;33:1-5 View Article PubMed/NCBI
  17. Lindblom P, Rafter I, Copley C, Andersson U, Hedberg JJ, Berg AL. Isoforms of alanine aminotransferases in human tissues and serum - Differential tissue expression using novel antibodies. Arch Biochem Biophys 2007;466:66-77 View Article PubMed/NCBI
  18. Russmann S, Kullak-Ublick GA, Grattagliano I. Current Concepts of Mechanisms in Drug-Induced Hepatotoxicity. Curr Med Chem 2009;16:3041-3053 View Article PubMed/NCBI
  19. Pasipanodya JG, Gumbo T. Clinical and Toxicodynamic Evidence that High-Dose Pyrazinamide Is Not More Hepatotoxic than the Low Doses Currently Used. Antimicrob Agents Chemother 2010;54:2847-2854 View Article PubMed/NCBI
  20. Russmann S, Kullak-Ublick GA, Grattagliano I. Current concepts of mechanisms in drug-induced hepatotoxicity. Curr Med Chem 2009;16:3041-3053 View Article PubMed/NCBI
  21. Tarantino G, Di Minno MND, Capone D. Drug-induced liver injury: Is it somehow foreseeable?. World J Gastroenterol 2009;15:2817-2833 View Article PubMed/NCBI
  22. Larson AM. Acetaminophen hepatotoxicity. Clin Liver Dis 2007;11:525-548, vi View Article PubMed/NCBI
  23. van Swelm RPL, Laarakkers CMM, van der Kuur EC, Morava-Kozicz E, Wevers RA, Augustijn KD. Identification of Novel Translational Urinary Biomarkers for Acetaminophen-Induced Acute Liver Injury Using Proteomic Profiling in Mice. Plos One 2012;7:e49524 View Article PubMed/NCBI
  24. Ryan PM, Bourdi M, Korrapati MC, Proctor WR, Vasquez RA, Yee SB. Endogenous Interleukin-4 Regulates Glutathione Synthesis Following Acetaminophen-Induced Liver Injury in Mice. Chem Res Toxicol 2012;25:83-93 View Article PubMed/NCBI
  25. Martin-Murphy BV, Holt MP, Ju C. The role of damage associated molecular pattern molecules in acetaminophen-induced liver injury in mice. Toxicol Lett 2010;192:387-394 View Article PubMed/NCBI
  26. Yin H, Cheng LL, Holt M, Hail N, MacLaren R, Ju C. Lactoferrin Protects Against Acetaminophen-induced Liver Injury in Mice. Hepatology 2010;51:1007-1016 View Article PubMed/NCBI
  27. Ganey PE, Luyendyk JP, Maddox JF, Roth RA. Adverse hepatic drug reactions: inflammatory episodes as consequence and contributor. Chem Biol Interact 2004;150:35-51 View Article PubMed/NCBI
  28. Kaplowitz N. Idiosyncratic drug hepatotoxicity. Nat Rev Drug Discov 2005;4:489-499 View Article PubMed/NCBI
  29. Uetrecht J. Idiosyncratic drug reactions: Current understanding. Annu Rev Pharmacol 2007;47:513-539 View Article PubMed/NCBI
  30. Cosgrove BD, King BM, Hasan MA, Alexopoulos LG, Farazi PA, Hendriks BS. Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity. Toxicol Appl Pharmacol 2009;237:317-330 View Article PubMed/NCBI
  31. Peters TS. Do preclinical testing strategies help predict human hepatotoxic potentials. Toxicol Pathol 2005;33:146-154 View Article PubMed/NCBI
  32. Uetrecht J. Screening for the potential of a drug candidate to cause idiosyncratic drug reactions. Drug Discov Today 2003;8:832-837 View Article PubMed/NCBI
  33. Lucena MI, Andrade RJ, Martinez C, Ulzurrun E, Garcia-Martin E, Borraz Y. Glutathione S-transferase M1 and T1 null genotypes increase susceptibility to idiosyncratic drug-induced liver injury. Hepatology 2008;48:588-596 View Article PubMed/NCBI
  34. Andrade RJ, Lucena MI, Kaplowitz N, Garcia-Munoz B, Borraz Y, Pachkoria K. Outcome of acute idiosyncratic drug-induced liver injury: Long-term follow-up in a hepatotoxicity registry. Hepatology 2006;44:1581-1588 View Article PubMed/NCBI
  35. Uetrecht J. Immunoallergic Drug-Induced Liver Injury in Humans. Semin Liver Dis 2009;29:383-392 View Article PubMed/NCBI
  36. Lammert C, Bjornsson E, Niklasson A, Chalasani N. Oral Medications with Significant Hepatic Metabolism at Higher Risk for Hepatic Adverse Events. Hepatology 2010;51:615-620 View Article PubMed/NCBI
  37. Daly AK. Drug-induced liver injury: past, present and future. Pharmacogenomics 2010;11:607-611 View Article PubMed/NCBI
  38. Daly AK, Donaldson PT, Bhatnagar P, Shen YF, Pe'er I, Floratos A. HLA-B(star)5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet 2009;41:816-819 View Article PubMed/NCBI
  39. Singer JB, Lewitzky S, Leroy E, Yang F, Zhao XJ, Klickstein L. A genome-wide study identifies HLA alleles associated with lumiracoxib-related liver injury. Nat Genet 2010;42:711-714 View Article PubMed/NCBI
  40. Pachkoria K, Lucena MI, Ruiz-Cabello F, Crespo E, Cabello MR, Andrade RJ. Genetic polymorphisms of CYP2C9 and CYP2C19 are not related to drug-induced idiosyncratic liver injury (DILI). Brit J Pharmacol 2007;150:808-815 View Article PubMed/NCBI
  41. Usui T, Mise M, Hashizume T, Yabuki M, Komuro S. Evaluation of the Potential for Drug-Induced Liver Injury Based on in Vitro Covalent Binding to Human Liver Proteins. Drug Metab Dispos 2009;37:2383-2392 View Article PubMed/NCBI
  42. Makarova SI. Human N-acetyltransferases and drug-induced hepatotoxicity. Curr Drug Metab 2008;9:538-545 View Article PubMed/NCBI
  43. Shapiro MA, Lewis JH. Causality assessment of drug-induced hepatotoxicity: promises and pitfalls. ClinLiver Dis 2007;11:477-505, v View Article PubMed/NCBI
  44. Chalasani N, Bjornsson E. Risk factors for idiosyncratic drug-induced liver injury. Gastroenterology 2010;138:2246-59 View Article PubMed/NCBI
  45. Tajiri K, Shimizu Y. Practical guidelines for diagnosis and early management of drug-induced liver injury. World J Gastroenterol 2008;14:6774-6785 View Article PubMed/NCBI
  46. Pollock NR, Rolland JP, Kumar S, Beattie PD, Jain S, Noubary F. A Paper-Based Multiplexed Transaminase Test for Low-Cost, Point-of-Care Liver Function Testing. Sci Transl Med 2012;4:152ra129 View Article PubMed/NCBI
  47. Souza LJ, Alves JG, Nogueira RM, Gicovate Neto C, Bastos DA, Siqueira EW. Aminotransferase changes and acute hepatitis in patients with dengue fever: analysis of 1,585 cases. Braz J Infect Dis 2004;8:156-163 View Article PubMed/NCBI
  48. Kuo CH, Tai DI, Chang-Chien CS, Lan CK, Chiou SS, Liaw YF. Liver biochemical tests and dengue fever. Am JTrop Med Hyg 1992;47:265-270 View Article PubMed/NCBI
  49. Xu HM, Chen Y, Xu J, Zhou Q. Drug-induced liver injury in hospitalized patients with notably elevated alanine aminotransferase. World J Gastroenterol 2012;18:5972-2978 View Article PubMed/NCBI
  50. David S, Hamilton JP. Drug-induced Liver Injury. US Gastroenterol Hepatol Rev 2010;6:73-80 View Article PubMed/NCBI
  51. Tran T, Lee WM. DILI: New Insights into Diagnosis and Management. Curr Hepat Rep 2013;12:53-58 View Article PubMed/NCBI
  52. Shi Q, Hong H, Senior J, Tong W. Biomarkers for drug-induced liver injury. Expert Rev Gastroenterol Hepatol 2010;4:225-434 View Article PubMed/NCBI
  53. Nathwani RA, Pais S, Reynolds TB, Kaplowitz N. Serum alanine aminotransferase in skeletal muscle diseases. Hepatology 2005;41:380-382 View Article PubMed/NCBI
  54. Shabaneh Al-Tamimi HA, McDonald R. Elevated alanine aminotransferase levels associated with polymyositis: can this be due to muscle injury?. J Clin Rheumatol 2008;14:363-364 View Article PubMed/NCBI
  55. Zed PJ, Krenzelok EP. Treatment of acetaminophen overdose. Am J Health Syst Pharm 1999;56:1081-1091 View Article PubMed/NCBI
  56. McMillian M, Nie AY, Parker JB, Leone A, Bryant S, Kemmerer M. A gene expression signature for oxidant stress/reactive metabolites in rat liver. Biochem Pharmacol 2004;68:2249-2261 View Article PubMed/NCBI
  57. Hirode M, Omura K, Kiyosawa N, Uehara T, Shimuzu T, Ono A. Gene expression profiling in rat liver treated with various hepatotoxic-compounds inducing coagulopathy. J Toxicol Sci 2009;34:281-293 View Article PubMed/NCBI
  58. Ozer J, Ratner M, Shaw M, Bailey W, Schomaker S. The current state of serum biomarkers of hepatotoxicity. Toxicology 2008;245:194-205 View Article PubMed/NCBI
  59. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004;116:281-297 View Article PubMed/NCBI
  60. Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993;75:843-854 View Article PubMed/NCBI
  61. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell 2009;136:215-233 View Article PubMed/NCBI
  62. Ambros V. The functions of animal microRNAs. Nature 2004;431:350-355 View Article PubMed/NCBI
  63. Ambros V. MicroRNA pathways in flies and worms: growth, death, fat, stress, and timing. Cell 2003;113:673-676 View Article PubMed/NCBI
  64. Lawrie CH, Gal S, Dunlop HM, Pushkaran B, Liggins AP, Pulford K. Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma. Brit J Haematol 2008;141:672-675 View Article PubMed/NCBI
  65. Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL. Circulating microRNAs as stable blood-based markers for cancer detection. P Natl Acad Sci U S A 2008;105:10513-10518 View Article PubMed/NCBI
  66. Chen X, Ba Y, Ma LJ, Cai X, Yin Y, Wang KH. Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res 2008;18:997-1006 View Article PubMed/NCBI
  67. Gilad S, Meiri E, Yogev Y, Benjamin S, Lebanony D, Yerushalmi N. Serum microRNAs are promising novel biomarkers. Plos One 2008;3:e3148 View Article PubMed/NCBI
  68. Garzon R, Calin GA, Croce CM. MicroRNAs in Cancer. Annu Rev Med 2009;60:167-179 View Article PubMed/NCBI
  69. Ng E, Chong W, Jin H, Lam E, Shin V, Yu J. Differential expression of microRNAs in plasma of patients with colorectal cancer: a potential marker for colorectal cancer screening. Gut 2009;58:1375-1381 View Article PubMed/NCBI
  70. Zen K, Zhang C. Circulating microRNAs: a novel class of biomarkers to diagnose and monitor human cancers. Med Res Rev 2012;32:326-348 View Article PubMed/NCBI
  71. Tung J. Exploring microRNA biomarkers for disease monitoring and response to therapy. Bioanalysis 2012;4:2204 View Article PubMed/NCBI
  72. Fukushima T, Hamada Y, Yamada H, Horii I. Changes of microRNA expression in rat liver treated by acetaminophen or carbon tetrachloride–regulating role of micro-RNA for RNA expression. J Toxicol Sci 2007;32:401-409 View Article PubMed/NCBI
  73. Pogribny IP, Tryndyak VP, Boyko A, Rodriguez-Juarez R, Beland FA, Kovalchuk O. Induction of microRNAome deregulation in rat liver by long-term tamoxifen exposure. Mutat Res 2007;619:30-37 View Article PubMed/NCBI
  74. Yoshioka W, Higashiyama W, Tohyama C. Involvement of microRNAs in dioxin-induced liver damage in the mouse. Toxicol Sci 2011;122:457-465 View Article PubMed/NCBI
  75. Endo S, Yano A, Fukami T, Nakajima M, Yokoi T. Involvement of miRNAs in the early phase of halothane-induced liver injury. Toxicology 2014;319:75-84 View Article PubMed/NCBI
  76. Tsuchiya Y, Nakajima M, Takagi S, Taniya T, Yokoi T. MicroRNA regulates the expression of human cytochrome P450 1B1. Cancer Res 2006;66:9090-9098 View Article PubMed/NCBI
  77. Komagata S, Nakajima M, Takagi S, Mohri T, Taniya T, Yokoi T. Human CYP24 catalyzing the inactivation of calcitriol is post-transcriptionally regulated by miR-125b. Mol Pharmacol 2009;76:702-709 View Article PubMed/NCBI
  78. Yokoi T, Nakajima M. Toxicological implications of modulation of gene expression by microRNAs. Toxicol Sci 2011;123:1-14 View Article PubMed/NCBI
  79. Yokoi T, Nakajima M. microRNAs as mediators of drug toxicity. Annu Rev Pharmacol Toxicol 2013;53:377-400 View Article PubMed/NCBI
  80. Wang K, Zhang S, Marzolf B, Troisch P, Brightman A, Hu Z. Circulating microRNAs, potential biomarkers for drug-induced liver injury. Proc Natl Acad Sci U S A 2009;106:4402-4407 View Article PubMed/NCBI
  81. Zhang Y, Jia Y, Zheng R, Guo Y, Wang Y, Guo H. Plasma microRNA-122 as a biomarker for viral-, alcohol-, and chemical-related hepatic diseases. Clin Chem 2010;56:1830-1838 View Article PubMed/NCBI
  82. Bala S, Petrasek J, Mundkur S, Catalano D, Levin I, Ward J. Circulating microRNAs in exosomes indicate hepatocyte injury and inflammation in alcoholic, drug-induced, and inflammatory liver diseases. Hepatology 2012;56:1946-1957 View Article PubMed/NCBI
  83. Ward J, Bala S, Petrasek J, Szabo G. Plasma microRNA profiles distinguish lethal injury in acetaminophen toxicity: a research study. World J Gastroenterol 2012;18:2798-2804 View Article PubMed/NCBI
  84. Shi Q, Yang X, Mendrick DL. Hopes and challenges in using miRNAs as translational biomarkers for drug-induced liver injury. Biomark Med 2013;7:307-315 View Article PubMed/NCBI
  85. Yamaura Y, Nakajima M, Takagi S, Fukami T, Tsuneyama K, Yokoi T. Plasma microRNA profiles in rat models of hepatocellular injury, cholestasis, and steatosis. Plos One 2012;7:e30250 View Article PubMed/NCBI
  86. Su YW, Chen X, Jiang ZZ, Wang T, Wang C, Zhang Y. A panel of serum microRNAs as specific biomarkers for diagnosis of compound- and herb-induced liver injury in rats. Plos One 2012;7:e37395 View Article PubMed/NCBI
  87. Starckx S, Batheja A, Verheyen GR, Jonghe SD, Steemans K, Dijck BV. Evaluation of miR-122 and other biomarkers in distinct acute liver injury in rats. Toxicol Pathol 2013;41:795-804 View Article PubMed/NCBI
  88. Weber JA, Baxter DH, Zhang S, Huang DY, Huang KH, Lee MJ. The microRNA spectrum in 12 body fluids. Clin Chem 2010;56:1733-1741 View Article PubMed/NCBI
  89. Lorenzen JM, Thum T. Circulating and urinary microRNAs in kidney disease. Clin J Am Soc Nephrol 2012;7:1528-1533 View Article PubMed/NCBI
  90. Yun SJ, Jeong P, Kim WT, Kim TH, Lee YS, Song PH. Cell-free microRNAs in urine as diagnostic and prognostic biomarkers of bladder cancer. Int J Oncol 2012;41:1871-1878 View Article PubMed/NCBI
  91. Yang X, Greenhaw J, Shi Q, Su Z, Qian F, Davis K. Identification of urinary microRNA profiles in rats that may diagnose hepatotoxicity. Toxicol Sci 2012;125:335-344 View Article PubMed/NCBI
  92. Starkey Lewis PJ, Dear J, Platt V, Simpson KJ, Craig DG, Antoine DJ. Circulating microRNAs as potential markers of human drug-induced liver injury. Hepatology 2011;54:1767-1776 View Article PubMed/NCBI
  93. Jetten MJ, Gaj S, Ruiz-Aracama A, de Kok TM, van Delft JH, Lommen A. 'Omics analysis of low dose acetaminophen intake demonstrates novel response pathways in humans. Toxicol Appl Pharmacol 2012;259:320-328 View Article PubMed/NCBI
  94. Antoine DJ, Dear JW, Lewis PS, Platt V, Coyle J, Masson M. Mechanistic biomarkers provide early and sensitive detection of acetaminophen-induced acute liver injury at first presentation to hospital. Hepatology 2013;58:777-787 View Article PubMed/NCBI
  95. Thulin P, Nordahl G, Gry M, Yimer G, Aklillu E, Makonnen E. Keratin-18 and microRNA-122 complement alanine aminotransferase as novel safety biomarkers for drug-induced liver injury in two human cohorts. Liver Int 2014;34:367-378 View Article PubMed/NCBI
  96. Ding XF, Ding JV, Ning J, Yi F, Chen JK, Zhao DY. Circulating microRNA-122 as a potential biomarker for liver injury. Mol Med Rep 2012;5:1428-1432 View Article PubMed/NCBI
  97. Esau C, Davis S, Murray SF, Yu XX, Pandey SK, Pear M. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab 2006;3:87-98 View Article PubMed/NCBI
  98. Krutzfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M. Silencing of microRNAs in vivo with ‘antagomirs’. Nature 2005;438:685-689 View Article PubMed/NCBI
  99. Jopling CL, Yi M, Lancaster AM, Lemon SM, Sarnow P. Modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA. Science 2005;309:1577-1581 View Article PubMed/NCBI
  100. Lardizabal MN, Nocito AL, Daniele SM, Ornella LA, Palatnik JF, Veggi LM. Reference genes for real-time PCR quantification of microRNAs and messenger RNAs in rat models of hepatotoxicity. Plos One 2012;7:e36323 View Article PubMed/NCBI
  101. Wang Y, Tang N, Hui T, Wang S, Zeng X, Li H. Identification of endogenous reference genes for RT-qPCR analysis of plasma microRNAs levels in rats with acetaminophen-induced hepatotoxicity. J Appl Toxicol 2013;33:1330-1336 View Article PubMed/NCBI

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