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Cirronis M, Schneemann S, Pettie J, Mannaioni G, Dear JW. Evaluation of capillary miR-122 as a prognostic biomarker of paracetamol-induced liver toxicity. Mol Biol Rep 2024; 51:548. [PMID: 38642142 DOI: 10.1007/s11033-024-09327-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 02/07/2024] [Indexed: 04/22/2024]
Abstract
INTRODUCTION Paracetamol (acetaminophen) overdose is a leading cause of acute liver failure in many Western countries. Diagnostic tools for this poisoning may be suboptimal in some cases and new biomarkers have been investigated. We investigated the role of capillary microRNA-122 (miR-122) as a prognostic biomarker of liver injury in the clinical management of patients with paracetamol overdose. METHODS In a paracetamol overdose patient cohort, miR-122 was measured by quantitative polymerase chain reaction in a blood drop obtained by a finger prick at the end of an antidote cycle treatment with N-acetylcysteine treatment (12 h). Liver injury was defined as serum alanine aminotransferase (ALT) activity > 100 IU/L collected at 10 or 20 h after the start of treatment. Pearson's correlation analyses were performed. RESULTS In patients with paracetamol overdose, capillary miR-122 was positively correlated with ALT measured at 10 h and at 20 h (r = 0.83, P < 0.0001; r = 0.96, P < 0.0001, respectively). CONCLUSION This work supports the potential use of capillary miR-122 as a prognostic biomarker of liver injury throughout clinical management of patients with paracetamol overdose. Capillary miR-122 can be measured in a blood drop collected by a finger prick, a minimally invasive diagnostic test for patient stratification.
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Affiliation(s)
- Marco Cirronis
- Edinburgh Clinical Toxicology, Royal Infirmary of Edinburgh, Edinburgh, UK.
- Department of Neuroscience, Psychiatry, Drug Area and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, Florence, Italy.
- Bergamo Poison Control Center & Teratology Information Service, ASST Papa Giovanni XXXIII Hospital, Bergamo, Italy.
| | - Sarah Schneemann
- Edinburgh Clinical Toxicology, Royal Infirmary of Edinburgh, Edinburgh, UK
- Julius Center for Health Sciences and Primary Care, Department of Medical Humanities, University Medical Center Utrecht, 3508 GA, Utrecht, Netherlands
| | - Janice Pettie
- Edinburgh Clinical Toxicology, Royal Infirmary of Edinburgh, Edinburgh, UK
- Pharmacology, Toxicology and Therapeutics, University/BHF Centre for Cardiovascular Science, Edinburgh University, Edinburgh, UK
| | - Guido Mannaioni
- Department of Neuroscience, Psychiatry, Drug Area and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, Florence, Italy
| | - James W Dear
- Edinburgh Clinical Toxicology, Royal Infirmary of Edinburgh, Edinburgh, UK
- Pharmacology, Toxicology and Therapeutics, University/BHF Centre for Cardiovascular Science, Edinburgh University, Edinburgh, UK
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Marín-Romero A, Regele V, Kolanovic D, Hofner M, Díaz-Mochón JJ, Nöhammer C, Pernagallo S. MAGPIX and FLEXMAP 3D Luminex platforms for direct detection of miR-122-5p through dynamic chemical labelling. Analyst 2023; 148:5658-5666. [PMID: 37807710 DOI: 10.1039/d3an01250f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Abstract
MicroRNAs (miRs) have emerged as promising biomarkers for diagnosing and predicting the prognosis of liver injury. This study aimed to compare the performance of two Luminex platforms, MAGPIX and FLEXMAP 3D, utilizing the innovative Dynamic Chemical Labelling (DCL) technology for direct detection and analysis of miR-122-5p in serum samples from patients with liver injury. Serum samples were collected from four patients with liver injury and four healthy controls. The levels of miR-122-5p were measured using the DCL method on both MAGPIX and FLEXMAP 3D platforms. The performance evaluation included the limit of detection (LOD), intra-assay and inter-assay precision, as well as accuracy. The results demonstrated that both platforms exhibited high sensitivity and specificity in detecting miR-122-5p in serum samples from patients with liver injury. However, FLEXMAP 3D indicated a lower LOD compared to MAGPIX. The precision of miR-122-5p detection was similar between the two platforms. In conclusion, both MAGPIX and FLEXMAP 3D Luminex platforms, in conjunction with DCL reagents, proved to be reliable and sensitive tools for detecting miR-122-5p in serum samples from patients with liver injury. Although both platforms were effective, FLEXMAP 3D exhibited slightly better performance, suggesting its preference for miR detection in clinical settings. These findings offer valuable insights for selecting the appropriate Luminex platform for miR detection in patients with liver injury and beyond.
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Affiliation(s)
- Antonio Marín-Romero
- DESTINA Genomica S.L. Parque Tecnológico Ciencias de la Salud (PTS), Edificio BIC, Avenida de la Innovación 1, Granada 18016, Spain.
| | - Valerie Regele
- Austrian Institute of Technology GmbH, Center for Health and Bioresources, Competence Unit Molecular Diagnostics, Vienna, Austria
| | - Dajana Kolanovic
- Austrian Institute of Technology GmbH, Center for Health and Bioresources, Competence Unit Molecular Diagnostics, Vienna, Austria
| | - Manuela Hofner
- Austrian Institute of Technology GmbH, Center for Health and Bioresources, Competence Unit Molecular Diagnostics, Vienna, Austria
| | - Juan José Díaz-Mochón
- Department of Medicinal & Organic Chemistry, Faculty of Pharmacy, University of Granada, Campus de Cartuja s/n, Granada, Spain
- GENYO Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government., PTS Granada - Avenida de la Ilustración, 114, 18016, Granada, Spain
- Unit of Excellence in Chemistry Applied to Biomedicine and the Environment of the University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain
| | - Christa Nöhammer
- Austrian Institute of Technology GmbH, Center for Health and Bioresources, Competence Unit Molecular Diagnostics, Vienna, Austria
| | - Salvatore Pernagallo
- DESTINA Genomica S.L. Parque Tecnológico Ciencias de la Salud (PTS), Edificio BIC, Avenida de la Innovación 1, Granada 18016, Spain.
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Shin HK, Huang R, Chen M. In silico modeling-based new alternative methods to predict drug and herb-induced liver injury: A review. Food Chem Toxicol 2023; 179:113948. [PMID: 37460037 PMCID: PMC10640386 DOI: 10.1016/j.fct.2023.113948] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 07/10/2023] [Accepted: 07/14/2023] [Indexed: 07/25/2023]
Abstract
New approach methods (NAMs) have been developed to predict a wide range of toxicities through innovative technologies. Liver injury is one of the most extensively studied endpoints due to its severity and frequency, occurring among populations that consume drugs or dietary supplements. In this review, we focus on recent developments of in silico modeling for liver injury prediction using deep learning and in vitro data based on adverse outcome pathways (AOPs). Despite these models being mainly developed using datasets generated from drug-like molecules, they were also applied to the prediction of hepatotoxicity caused by herbal products. As deep learning has achieved great success in many different fields, advanced machine learning algorithms have been actively applied to improve the accuracy of in silico models. Additionally, the development of liver AOPs, combined with big data in toxicology, has been valuable in developing in silico models with enhanced predictive performance and interpretability. Specifically, one approach involves developing structure-based models for predicting molecular initiating events of liver AOPs, while others use in vitro data with structure information as model inputs for making predictions. Even though liver injury remains a difficult endpoint to predict, advancements in machine learning algorithms and the expansion of in vitro databases with relevant biological knowledge have made a huge impact on improving in silico modeling for drug-induced liver injury prediction.
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Affiliation(s)
- Hyun Kil Shin
- Department of Predictive Toxicology, Korea Institute of Toxicology (KIT), 34114, Daejeon, Republic of Korea
| | - Ruili Huang
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, MD, 20850, USA.
| | - Minjun Chen
- Division of Bioinformatics and Biostatistics, National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration, 3900 NCTR Rd., Jefferson, AR, 72079, USA.
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Doghish AS, Elballal MS, Elazazy O, Elesawy AE, Elrebehy MA, Shahin RK, Midan HM, Sallam AAM. The role of miRNAs in liver diseases: Potential therapeutic and clinical applications. Pathol Res Pract 2023; 243:154375. [PMID: 36801506 DOI: 10.1016/j.prp.2023.154375] [Citation(s) in RCA: 67] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/10/2023] [Accepted: 02/11/2023] [Indexed: 02/16/2023]
Abstract
MicroRNAs (miRNAs) are a class of short, non-coding RNAs that function post-transcriptionally to regulate gene expression by binding to particular mRNA targets and causing destruction of the mRNA or translational inhibition of the mRNA. The miRNAs control the range of liver activities, from the healthy to the unhealthy. Considering that miRNA dysregulation is linked to liver damage, fibrosis, and tumorigenesis, miRNAs are a promising therapeutic strategy for the evaluation and treatment of liver illnesses. Recent findings on the regulation and function of miRNAs in liver diseases are discussed, with an emphasis on miRNAs that are highly expressed or enriched in hepatocytes. Alcohol-related liver illness, acute liver toxicity, viral hepatitis, hepatocellular carcinoma, liver fibrosis, liver cirrhosis, and exosomes in chronic liver disease all emphasize the roles and target genes of these miRNAs. We briefly discuss the function of miRNAs in the etiology of liver diseases, namely in the transfer of information between hepatocytes and other cell types via extracellular vesicles. Here we offer some background on the use of miRNAs as biomarkers for the early prognosis, diagnosis, and assessment of liver diseases. The identification of biomarkers and therapeutic targets for liver disorders will be made possible by future research into miRNAs in the liver, which will also help us better understand the pathogeneses of liver diseases.
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Affiliation(s)
- Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
| | - Mohammed S Elballal
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Ola Elazazy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Ahmed E Elesawy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Mahmoud A Elrebehy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt.
| | - Reem K Shahin
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Heba M Midan
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Al-Aliaa M Sallam
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
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Abdel Halim AS, Rudayni HA, Chaudhary AA, Ali MAM. MicroRNAs: Small molecules with big impacts in liver injury. J Cell Physiol 2023; 238:32-69. [PMID: 36317692 DOI: 10.1002/jcp.30908] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 09/30/2022] [Accepted: 10/14/2022] [Indexed: 11/07/2022]
Abstract
A type of small noncoding RNAs known as microRNAs (miRNAs) fine-tune gene expression posttranscriptionally by binding to certain messenger RNA targets. Numerous physiological processes in the liver, such as differentiation, proliferation, and apoptosis, are regulated by miRNAs. Additionally, there is growing evidence that miRNAs contribute to liver pathology. Extracellular vesicles like exosomes, which contain secreted miRNAs, may facilitate paracrine and endocrine communication between various tissues by changing the gene expression and function of distal cells. The use of stable miRNAs as noninvasive biomarkers was made possible by the discovery of these molecules in body fluids. Circulating miRNAs reflect the conditions of the liver that are abnormal and may serve as new biomarkers for the early detection, prognosis, and evaluation of liver pathological states. miRNAs are appealing therapeutic targets for a range of liver disease states because altered miRNA expression is associated with deregulation of the liver's metabolism, liver damage, liver fibrosis, and tumor formation. This review provides a comprehensive review and update on miRNAs biogenesis pathways and mechanisms of miRNA-mediated gene silencing. It also outlines how miRNAs affect hepatic cell proliferation, death, and regeneration as well as hepatic detoxification. Additionally, it highlights the diverse functions that miRNAs play in the onset and progression of various liver diseases, including nonalcoholic fatty liver disease, alcoholic liver disease, fibrosis, hepatitis C virus infection, and hepatocellular carcinoma. Further, it summarizes the diverse liver-specific miRNAs, illustrating the potential merits and possible caveats of their utilization as noninvasive biomarkers and appealing therapeutic targets for liver illnesses.
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Affiliation(s)
- Alyaa S Abdel Halim
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Hassan Ahmed Rudayni
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Anis Ahmad Chaudhary
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Mohamed A M Ali
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt.,Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
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Zajkowska M, Mroczko B. Chemokines in Primary Liver Cancer. Int J Mol Sci 2022; 23:ijms23168846. [PMID: 36012108 PMCID: PMC9408270 DOI: 10.3390/ijms23168846] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/04/2022] [Accepted: 08/08/2022] [Indexed: 11/16/2022] Open
Abstract
The liver is responsible for extremely important functions in the human body. In the liver’s structure, we distinguish between connective tissue (stroma) and parenchyma, the latter of which is formed from the basic structural and functional units of the liver—hepatocytes. There are many factors, that negatively affect the liver cells, contributing to their damage. This may lead to fibrosis, liver failure and, in consequence, primary liver cancer, which is the sixth most commonly diagnosed malignancy and the fourth leading cause of cancer death worldwide. Chemokines are a large family of secreted proteins. Their main role is to direct the recruitment and migration of cells to sites of inflammation or injury. Some authors suggest that these proteins might play a potential role in the development of many malignancies, including primary liver cancer. The aim of this study was to evaluate and summarize the knowledge regarding liver diseases, especially primary liver cancer (HCC) and the participation of chemokines in the development of this malignancy. Chemokines involved in the initiation of this type of tumor belong mainly to the CC and CXC chemokines. Their significant role in the course of hepatocellular carcinoma proves their usefulness in detecting and monitoring the course and treatment in patients with this disease.
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Affiliation(s)
- Monika Zajkowska
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
- Correspondence: ; Tel.: +48-686-5168; Fax: +48-686-5169
| | - Barbara Mroczko
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
- Department of Biochemical Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
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Khafagy HF, AbuSeada AN, Shash AM, Elayashy M, El-Araby RE, Sabry OM, Montasser AY, Mohamed MS, Ebied RS, Samhan YM. Effects of Desflurane exposure and Laparotomy on genomic biomarkers and hepatic histopathology in an experimentally induced liver injury model: A pilot study. EGYPTIAN JOURNAL OF ANAESTHESIA 2022. [DOI: 10.1080/11101849.2022.2069219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Affiliation(s)
- Hanan F. Khafagy
- Department of Anesthesia and Surgical Intensive Care, Theodor Bilharz Research Institute, Ministry of Higher Education and Scientific Research, Giza, Egypt
| | - AbdulRahman N. AbuSeada
- Department of Anesthesia and Surgical Intensive Care, Theodor Bilharz Research Institute, Ministry of Higher Education and Scientific Research, Giza, Egypt
| | - Ahmed M. Shash
- Department of Anesthesia, Faculty of Medicine, Cairo University, Ministry of Higher Education and Scientific Research, Cairo, Egypt
| | - Mohamed Elayashy
- Department of Anesthesia, Faculty of Medicine, Cairo University, Ministry of Higher Education and Scientific Research, Cairo, Egypt
| | - Rady E. El-Araby
- Molecular Biology, Central Lab, Theodor Bilharz Research Institute, Ministry of Higher Education and Scientific Research, Giza, Egypt
| | - Omar M. Sabry
- Department of Hematology, Theodor Bilharz Research Institute, Ministry of Higher Education and Scientific Research, Giza, Egypt
| | - Ahmed Y. Montasser
- Department of Pathology, Theodor Bilharz Research Institute, Ministry of Higher Education and Scientific Research, Giza, Egypt
| | - Mohamed S. Mohamed
- Experimental Laboratory Unit Theodor Bilharz Research Institute, Ministry of Higher Education and Scientific Research, Giza, Egypt
| | - Reeham S. Ebied
- Department of Anesthesia and Surgical Intensive Care, Theodor Bilharz Research Institute, Ministry of Higher Education and Scientific Research, Giza, Egypt
| | - Yasser M. Samhan
- Department of Anesthesia and Surgical Intensive Care, Theodor Bilharz Research Institute, Ministry of Higher Education and Scientific Research, Giza, Egypt
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Kim C, Zhu S, Kouros-Mehr H, Khaldoyanidi S. Incidence of Elevated Aminotransferases With or Without Bilirubin Elevation During Treatment With Immune Checkpoint Inhibitors: A Retrospective Study of Patients From Community Oncology Clinics in the United States. Cureus 2022; 14:e24053. [PMID: 35573501 PMCID: PMC9095812 DOI: 10.7759/cureus.24053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/06/2022] [Indexed: 11/22/2022] Open
Abstract
Introduction The elevation of aminotransferase levels is regarded as an indicator of hepatocellular injury. The objective of this study was to describe real-world incidence of elevated aminotransferase levels with or without bilirubin elevation among patients treated with immune checkpoint inhibitors (ICIs) for solid tumors. Methods This retrospective cohort study used an electronic health record database representing > 1.5 million active United States (US) cancer patients and included patients diagnosed with any cancer between January 1, 2014 and March 31, 2019, and treated with one or more ICIs such as ipilimumab, tremelimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab. The frequency, onset, duration, management of grade ≥ 3 elevation of aminotransferase levels with or without bilirubin elevation events, progression rate from isolated elevation of aminotransferase levels (IAT) to elevated aminotransferase levels with elevated bilirubin (ATWB), and mortality were described. Results Overall, 69,140 patients received 85,433 treatment courses. A total of 1,799 (2.11%) IAT and 441 (0.52%) ATWB events were observed during treatment courses. The median onset was 51 and 42 days for IAT and ATWB, respectively, across treatment courses, and the median duration of both was approximately seven days. Approximately 5% (n=96) of IAT events progressed to ATWB in a median time of 11 days. The proportion of patients who received corticosteroids after elevated aminotransferase levels with or without bilirubin was ~37% (n=671/1,799 of IAT and n=147/441 of ATWB) and ~8% discontinued ICI treatment (n=118/1,799 of IAT and n=43/441 of ATWB). About 46% (n=68/147) of ATWB and and 25% (n=172/671) of IAT events treated with steroids led to death within 45 days. Similarly, 49% (n=21/43) of ATWB and 35% (n=42/118) of IAT events leading to treatment discontinuation led to death within 45 days. Conclusions Real-world data from oncology clinics in US suggest low incidence of grade ≥ 3 elevated aminotransferase levels with or without bilirubin elevation following treatment with ICIs. In most cases, ICI treatment was not discontinued and management of elevated aminotransferases consisted of corticosteroid treatment in one-third of cases.
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Affiliation(s)
- Christopher Kim
- Center for Observational Research, Amgen Inc., Thousand Oaks, USA
| | - Shao Zhu
- Biostatistics, Simulstat Inc., San Diego, USA
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Drug-Induced Liver Injury: Clinical Evidence of N-Acetyl Cysteine Protective Effects. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:3320325. [PMID: 34912495 PMCID: PMC8668310 DOI: 10.1155/2021/3320325] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 11/12/2021] [Accepted: 11/22/2021] [Indexed: 12/29/2022]
Abstract
Oxidative stress is a key pathological feature implicated in both acute and chronic liver diseases, including drug-induced liver injury (DILI). The latter describes hepatic injury arising as a direct toxic effect of administered drugs or their metabolites. Although still underreported, DILI remains a significant cause of liver failure, especially in developed nations. Currently, it is understood that mitochondrial-generated oxidative stress and abnormalities in phase I/II metabolism, leading to glutathione (GSH) suppression, drive the onset of DILI. N-Acetyl cysteine (NAC) has attracted a lot of interest as a therapeutic agent against DILI because of its strong antioxidant properties, especially in relation to enhancing endogenous GSH content to counteract oxidative stress. Thus, in addition to updating information on the pathophysiological mechanisms implicated in oxidative-induced hepatic injury, the current review critically discusses clinical evidence on the protective effects of NAC against DILI, including the reduction of patient mortality. Besides injury caused by paracetamol, NAC can also improve liver function in relation to other forms of liver injury such as those induced by excessive alcohol intake. The implicated therapeutic mechanisms of NAC extend from enhancing hepatic GSH levels to reducing biomarkers of paracetamol toxicity such as keratin-18 and circulating caspase-cleaved cytokeratin-18. However, there is still lack of evidence confirming the benefits of using NAC in combination with other therapies in patients with DILI.
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Segovia-Zafra A, Di Zeo-Sánchez DE, López-Gómez C, Pérez-Valdés Z, García-Fuentes E, Andrade RJ, Lucena MI, Villanueva-Paz M. Preclinical models of idiosyncratic drug-induced liver injury (iDILI): Moving towards prediction. Acta Pharm Sin B 2021; 11:3685-3726. [PMID: 35024301 PMCID: PMC8727925 DOI: 10.1016/j.apsb.2021.11.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 11/07/2021] [Accepted: 11/10/2021] [Indexed: 02/08/2023] Open
Abstract
Idiosyncratic drug-induced liver injury (iDILI) encompasses the unexpected harms that prescription and non-prescription drugs, herbal and dietary supplements can cause to the liver. iDILI remains a major public health problem and a major cause of drug attrition. Given the lack of biomarkers for iDILI prediction, diagnosis and prognosis, searching new models to predict and study mechanisms of iDILI is necessary. One of the major limitations of iDILI preclinical assessment has been the lack of correlation between the markers of hepatotoxicity in animal toxicological studies and clinically significant iDILI. Thus, major advances in the understanding of iDILI susceptibility and pathogenesis have come from the study of well-phenotyped iDILI patients. However, there are many gaps for explaining all the complexity of iDILI susceptibility and mechanisms. Therefore, there is a need to optimize preclinical human in vitro models to reduce the risk of iDILI during drug development. Here, the current experimental models and the future directions in iDILI modelling are thoroughly discussed, focusing on the human cellular models available to study the pathophysiological mechanisms of the disease and the most used in vivo animal iDILI models. We also comment about in silico approaches and the increasing relevance of patient-derived cellular models.
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Affiliation(s)
- Antonio Segovia-Zafra
- Unidad de Gestión Clínica de Gastroenterología, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga 29071, Spain
- Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid 28029, Spain
| | - Daniel E. Di Zeo-Sánchez
- Unidad de Gestión Clínica de Gastroenterología, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga 29071, Spain
| | - Carlos López-Gómez
- Unidad de Gestión Clínica de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Málaga 29010, Spain
| | - Zeus Pérez-Valdés
- Unidad de Gestión Clínica de Gastroenterología, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga 29071, Spain
| | - Eduardo García-Fuentes
- Unidad de Gestión Clínica de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Málaga 29010, Spain
| | - Raúl J. Andrade
- Unidad de Gestión Clínica de Gastroenterología, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga 29071, Spain
- Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid 28029, Spain
| | - M. Isabel Lucena
- Unidad de Gestión Clínica de Gastroenterología, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga 29071, Spain
- Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid 28029, Spain
- Platform ISCIII de Ensayos Clínicos, UICEC-IBIMA, Málaga 29071, Spain
| | - Marina Villanueva-Paz
- Unidad de Gestión Clínica de Gastroenterología, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga 29071, Spain
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Schofield AL, Brown JP, Brown J, Wilczynska A, Bell C, Glaab WE, Hackl M, Howell L, Lee S, Dear JW, Remes M, Reeves P, Zhang E, Allmer J, Norris A, Falciani F, Takeshita LY, Seyed Forootan S, Sutton R, Park BK, Goldring C. Systems analysis of miRNA biomarkers to inform drug safety. Arch Toxicol 2021; 95:3475-3495. [PMID: 34510227 PMCID: PMC8492583 DOI: 10.1007/s00204-021-03150-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023]
Abstract
microRNAs (miRNAs or miRs) are short non-coding RNA molecules which have been shown to be dysregulated and released into the extracellular milieu as a result of many drug and non-drug-induced pathologies in different organ systems. Consequently, circulating miRs have been proposed as useful biomarkers of many disease states, including drug-induced tissue injury. miRs have shown potential to support or even replace the existing traditional biomarkers of drug-induced toxicity in terms of sensitivity and specificity, and there is some evidence for their improved diagnostic and prognostic value. However, several pre-analytical and analytical challenges, mainly associated with assay standardization, require solutions before circulating miRs can be successfully translated into the clinic. This review will consider the value and potential for the use of circulating miRs in drug-safety assessment and describe a systems approach to the analysis of the miRNAome in the discovery setting, as well as highlighting standardization issues that at this stage prevent their clinical use as biomarkers. Highlighting these challenges will hopefully drive future research into finding appropriate solutions, and eventually circulating miRs may be translated to the clinic where their undoubted biomarker potential can be used to benefit patients in rapid, easy to use, point-of-care test systems.
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Affiliation(s)
- Amy L Schofield
- MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK
| | - Joseph P Brown
- MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK
| | - Jack Brown
- MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK
| | - Ania Wilczynska
- bit.bio, Babraham Research Campus, The Dorothy Hodgkin Building, Cambridge, CB22 3FH, UK
| | - Catherine Bell
- CVRM Safety, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden
| | - Warren E Glaab
- Merck & Co., Inc, 770 Sumneytown Pike, West Point, PA, 19486, USA
| | | | - Lawrence Howell
- GlaxoSmithKline (GSK), Stevenage, Greater Cambridge Area, UK
| | - Stephen Lee
- ABHI, 1 Duchess St, 4th Floor, Suite 2, London, W1W 6AN, UK
| | - James W Dear
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK
| | - Mika Remes
- Genomics EMEA, QIAGEN Aarhus, Prismet, Silkeborgvej 2, 8000, Aarhus C, Denmark
| | - Paul Reeves
- Arcis Biotechnology Limited, Suite S07, Techspace One, Sci-tech Daresbury, Keckwick Lane, Daresbury, Warrington, WA4 4AB, UK
| | - Eunice Zhang
- Wolfson Centre for Personalised Medicine, Department of Pharmacology and Therapeutics, University of Liverpool, Crown Street, Liverpool, L69 3BX, UK
| | - Jens Allmer
- Applied Bioinformatics, Bioscience, Wageningen University and Research, Droevendaalsesteeg 4, 6708 PB, Wageningen, The Netherlands
| | - Alan Norris
- MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK
| | - Francesco Falciani
- Computational Biology Facility, MerseyBio, University of Liverpool, Crown Street, Liverpool, L69 7ZB, UK
| | - Louise Y Takeshita
- Computational Biology Facility, MerseyBio, University of Liverpool, Crown Street, Liverpool, L69 7ZB, UK
| | - Shiva Seyed Forootan
- MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK
| | - Robert Sutton
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Biosciences Building, Crown Street, Liverpool, L69 7BE, UK
| | - B Kevin Park
- MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK
| | - Chris Goldring
- MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK.
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12
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Simultaneous Detection of Drug-Induced Liver Injury Protein and microRNA Biomarkers Using Dynamic Chemical Labelling on a Luminex MAGPIX System. ANALYTICA 2021. [DOI: 10.3390/analytica2040013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
Drug-induced liver injury (DILI) is a potentially fatal adverse event and a leading cause for pre- and post-marketing drug withdrawal. Several multinational DILI initiatives have now recommended a panel of protein and microRNA (miRNA) biomarkers that can detect early liver injury and inform about mechanistic basis. This manuscript describes the development of seqCOMBO, a unique combo-multiplexed assay which combines the dynamic chemical labelling approach and an antibody-dependant method on the Luminex MAGPIX system. SeqCOMBO enables a versatile multiplexing platform to perform qualitative and quantitative analysis of proteins and miRNAs in patient serum samples simultaneously. To the best of our knowledge, this is the first method to profile protein and miRNA biomarkers to diagnose DILI in a single-step assay.
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13
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Bessone F, Hernandez N, Tagle M, Arrese M, Parana R, Méndez-Sánchez N, Ridruejo E, Mendizabal M, Dagher L, Contreras F, Fassio E, Pessoa M, Brahm J, Silva M. Drug-induced liver injury: A management position paper from the Latin American Association for Study of the liver. Ann Hepatol 2021; 24:100321. [PMID: 33609753 DOI: 10.1016/j.aohep.2021.100321] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 01/18/2021] [Accepted: 01/18/2021] [Indexed: 02/06/2023]
Abstract
Idiosyncratic drug-induced liver injury (DILI) caused by xenobiotics (drugs, herbals and dietary supplements) is an uncommon cause of liver disease presenting with a wide range of phenotypes and disease severity, acute hepatitis mimicking viral hepatitis to autoimmune hepatitis, steatosis, fibrosis or rare chronic vascular syndromes. Disease severity ranges from asymptomatic liver test abnormalities to acute liver failure. DILI has been traditionally classified in predictable or intrinsic (dose-related) or unpredictable (not dose-related) mechanisms. Few prospective studies are assessing the real prevalence and incidence of hepatotoxicity in the general population. DILI registries represent useful networks used for the study of liver toxicity, aimed at improving the understanding of causes, phenotypes, natural history, and standardized definitions of hepatotoxicity. Although most of the registries do not carry out population-based studies, they may provide important data related to the prevalence of DILI, and also may be useful to compare features from different countries. With the support of the Spanish Registry of Hepatotoxicity, our Latin American Registry (LATINDILI) was created in 2011, and more than 350 DILI patients have been recruited to date. This position paper describes the more frequent drugs and herbs-induced DILI in Latin America, mainly focusing on several features of responsible medicaments. Also, we highlighted the most critical points on the management of hepatotoxicity in general and those based on findings from our Latin American experience in particular.
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Affiliation(s)
- Fernando Bessone
- Hospital Provincial del Centenario, Facultad de Medicina, Universidad Nacional de Rosario, Rosario, Argentina.
| | | | - Martin Tagle
- Universidad Peruana Cayetano Heredia, Lima, Peru
| | - Marco Arrese
- Pontificia Universidad Católica de chile, Santiago de Chile, Chile
| | | | - Nahum Méndez-Sánchez
- Liver Research Unit, Medica Sur Clinic & Foundation, Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico; Liver Research Unit, Medica Sur Clinic & Foundation, Mexico City, Mexico
| | - Ezequiel Ridruejo
- Centro de Educación Médica e Investigaciones Clínicas Norberto Quirno "CEMIC", Buenos Aires, Argentina
| | | | - Lucy Dagher
- Policlínica Metropolitana y CMDLT, Caracas, Venezuela
| | | | - Eduardo Fassio
- Hospital Nacional Prof. Alejandro Posadas, Provincia de Buenos Aires, Argentina
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14
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Metabolomic analysis to discriminate drug-induced liver injury (DILI) phenotypes. Arch Toxicol 2021; 95:3049-3062. [PMID: 34274980 PMCID: PMC8380240 DOI: 10.1007/s00204-021-03114-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 06/29/2021] [Indexed: 12/19/2022]
Abstract
Drug-induced liver injury (DILI) is an adverse toxic hepatic clinical reaction associated to the administration of a drug that can occur both at early clinical stages of drug development, as well after normal clinical usage of approved drugs. Because of its unpredictability and clinical relevance, it is of medical concern. Three DILI phenotypes (hepatocellular, cholestatic, and mixed) are currently recognized, based on serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) values. However, this classification lacks accuracy to distinguish among the many intermediate mixed types, or even to estimate the magnitude and progression of the injury. It was found desirable to have additional elements for better evaluation criteria of DILI. With this aim, we have examined the serum metabolomic changes occurring in 79 DILI patients recruited and monitored using established clinical criteria, along the course of the disease and until recovery. Results revealed that free and conjugated bile acids, and glycerophospholipids were among the most relevant metabolite classes for DILI phenotype characterization. Using an ensemble of PLS-DA models, metabolomic information was integrated into a ternary diagram to display the disease phenotype, the severity of the liver damage, and its progression. The modeling implemented and the use of such compiled information in an easily understandable and visual manner facilitates a straightforward DILI phenotyping and allow to monitor its progression and recovery prediction, usefully complementing the concise information drawn out by the ALT and ALP classification.
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15
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Becker MW, Schwambach KH, Lunardelli M, Blatt CR. Overview of drug induced liver injury in Brazil: What is the role of public health policy on the evidence? World J Gastrointest Pharmacol Ther 2021; 12:40-55. [PMID: 34046243 PMCID: PMC8134851 DOI: 10.4292/wjgpt.v12.i3.40] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 01/20/2021] [Accepted: 04/25/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Adverse drug reactions are responsible for increased costs and morbidity in the health system. Hepatotoxicity can be induced both by non-prescription drugs and by those used for chronic diseases. It is the main cause of safety-related drug marketing withdrawals and could be responsible for irreversible and fatal injuries. AIM To identify and to summarize Brazilian studies reporting the drug-induced liver injury. METHODS A systematic review of Brazilian studies was carried out until June 2020. It was found 32 studies, being 10 retrospective cohorts, 12 prospective cohorts, 5 cross-sectional, 3 case-control, one case series and one randomized clinical trial. In most studies were investigated tuberculosis patients followed by other infectious conditions like human immunodeficiency virus (HIV) and hepatitis C virus. The hepatotoxicity ranged from one to 57%, led by isoniazid, rifampicin, and pyrazinamide. Few studies reported algorithm to assess causality. In most studies, there were moderate outcomes and it was necessary drug interruption. However, few severe outcomes, such as chronic liver damage and liver transplantation were reported. RESULTS Twenty-two different criteria for hepatotoxicity were found. The great heterogeneity did not allow a meta-analysis. Standardization of parameter of drug-induced liver injury and greater effort in pharmacovigilance could contribute to learn more about drug-induced liver injury (DILI)'s epidemiology in Brazil. CONCLUSION The development of strategic public health policies seems to have an influence on the DILI scientific evidence in Brazil due to main studies are in HIV and tuberculosis line care, two strategic health policies in Brazil.
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Affiliation(s)
- Matheus William Becker
- Graduate Program in Medicine-Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, RS, Brazil
| | - Karin Hepp Schwambach
- Graduate Program in Medicine-Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, RS, Brazil
| | - Michele Lunardelli
- Graduate Program in Medicine-Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, RS, Brazil
| | - Carine Raquel Blatt
- Graduate Program in Medicine-Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, RS, Brazil
- Pharmacoscience Department, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, RS, Brazil
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16
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Greca RD, Cunha-Silva M, Costa LBE, Costa JGF, Mazo DFC, Sevá-Pereira T, Nascimento MMC, Pereira IE, Oliveira FC, Faria GAS, Neto FLP, Almeida JRS. Vanishing bile duct syndrome related to DILI and Hodgkin lymphoma overlap: A rare and severe case. Ann Hepatol 2021; 19:107-112. [PMID: 31537508 DOI: 10.1016/j.aohep.2019.06.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 06/03/2019] [Accepted: 06/10/2019] [Indexed: 02/04/2023]
Abstract
Vanishing bile duct syndrome is a rare acquired condition, characterized by progressive loss of intrahepatic bile ducts leading to ductopenia and cholestasis. It can be associated with infections, ischemia, drug adverse reactions, neoplasms, autoimmune disease, and allograft rejection. Prognosis is variable and depends on the etiology of bile duct injury. We report the case of a 25-year-old female with cholestatic hepatitis and concomitant intakes of hepatotoxic substances, such as garcinia, field horsetail, and ketoprofen. On suspicion of a drug-induced liver injury, the drugs were promptly withdrawn and ursodeoxycholic acid was started with initial clinical and laboratory improvement, and the patient was discharged from the hospital. One month later, she had a new increase in bilirubin levels and canalicular enzymes, requiring a liver biopsy that showed significant loss of intrahepatic bile ducts, which was compatible with vanishing bile duct syndrome. This was confirmed by using cytokeratin 19 on immunohistochemistry. There was subsequent lymph node enlargement in several chains, and relevant weight loss. Histological analysis of a cervical lymph node revealed nodular sclerosis-subtype classic Hodgkin lymphoma. In this setting, vanishing bile duct syndrome was related to Hodgkin lymphoma and a drug-induced liver injury overlap, leading to progressive cholestasis with a worse prognosis. The patient's response to chemotherapy was poor, requiring biological therapy with brentuximab vedotin. It is crucial for physicians to create a broad differential diagnosis in suspected vanishing bile duct syndrome patients, especially to rule out malignancies.
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Affiliation(s)
- Raquel D Greca
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil.
| | - Marlone Cunha-Silva
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Larissa B E Costa
- Department of Pathology, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Júlia G F Costa
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Daniel F C Mazo
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil; Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, University of São Paulo, School of Medicine, São Paulo, Brazil
| | - Tiago Sevá-Pereira
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Marlla M C Nascimento
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Isadora E Pereira
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Flávia C Oliveira
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Guilherme A S Faria
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Fernando L P Neto
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Jazon R S Almeida
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
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17
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Walker PA, Ryder S, Lavado A, Dilworth C, Riley RJ. The evolution of strategies to minimise the risk of human drug-induced liver injury (DILI) in drug discovery and development. Arch Toxicol 2020; 94:2559-2585. [PMID: 32372214 PMCID: PMC7395068 DOI: 10.1007/s00204-020-02763-w] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Accepted: 04/22/2020] [Indexed: 12/15/2022]
Abstract
Early identification of toxicity associated with new chemical entities (NCEs) is critical in preventing late-stage drug development attrition. Liver injury remains a leading cause of drug failures in clinical trials and post-approval withdrawals reflecting the poor translation between traditional preclinical animal models and human clinical outcomes. For this reason, preclinical strategies have evolved over recent years to incorporate more sophisticated human in vitro cell-based models with multi-parametric endpoints. This review aims to highlight the evolution of the strategies adopted to improve human hepatotoxicity prediction in drug discovery and compares/contrasts these with recent activities in our lab. The key role of human exposure and hepatic drug uptake transporters (e.g. OATPs, OAT2) is also elaborated.
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Affiliation(s)
- Paul A Walker
- Cyprotex Discovery Ltd., No.24 Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.
| | - Stephanie Ryder
- Cyprotex Discovery Ltd., No.24 Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK
| | - Andrea Lavado
- Cyprotex Discovery Ltd., No.24 Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK
| | - Clive Dilworth
- Cyprotex Discovery Ltd., No.24 Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.,Alderley Park Accelerator, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK
| | - Robert J Riley
- Cyprotex Discovery Ltd., No.24 Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK
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18
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Real M, Barnhill MS, Higley C, Rosenberg J, Lewis JH. Drug-Induced Liver Injury: Highlights of the Recent Literature. Drug Saf 2020; 42:365-387. [PMID: 30343418 DOI: 10.1007/s40264-018-0743-2] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Drug-induced liver injury (DILI), herbal-induced liver injury, and herbal and dietary supplement (HDS)-induced liver injury are an important aspect of drug safety. Knowledge regarding responsible drugs, mechanisms, risk factors, and the diagnostic tools to detect liver injury have continued to grow in the past year. This review highlights what we considered the most significant publications from among more than 1800 articles relating to liver injury from medications, herbal products, and dietary supplements in 2017 and 2018. The US Drug-Induced Liver Injury Network (DILIN) prospective study highlighted several areas of ongoing study, including the potential utility of human leukocyte antigens and microRNAs as DILI risk factors and new data on racial differences, the role of alcohol consumption, factors associated with prognosis, and updates on the clinical signatures of autoimmune DILI, thiopurines, and HDS agents. Novel data were also generated from the Spanish and Latin American DILI registries as well as from Chinese and Korean case series. A few new agents causing DILI were added to the growing list in the past 2 years, including sodium-glucose co-transporter-2 inhibitors, as were new aspects of chemotherapy-associated liver injury. A number of cases reported previously described hepatotoxins confirmed via the Roussel Uclaf Causality Assessment Method (RUCAM; e.g., norethisterone, methylprednisolone, glatiramer acetate) and/or the DILIN method (e.g., celecoxib, dimethyl fumarate). Additionally, much work centered on elucidating the pathophysiology of DILI, including the importance of bile salt export pumps and immune-mediated mechanisms. Finally, it must be noted that, while hundreds of new studies described DILI in 2017-2018, the quality of such reports must always be addressed. Björnsson reminds us to remain very critical of the data when addressing the future utility of a study, which is why it is so important to adhere to a standardized method such as RUCAM when determining DILI causality. While drug-induced hepatotoxicity remains a diagnosis of exclusion, the diverse array of publications that appeared in 2017 and 2018 provided important advances in our understanding of DILI, paving the way for our improved ability to make a more definitive diagnosis and risk assessment.
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Affiliation(s)
- Mark Real
- Division of Gastroenterology and Hepatology, Georgetown University Hospital, Washington, DC, USA
| | - Michele S Barnhill
- Department of Medicine, Georgetown University Hospital, Washington, DC, USA
| | - Cory Higley
- Department of Medicine, Georgetown University Hospital, Washington, DC, USA
| | - Jessica Rosenberg
- Department of Medicine, Georgetown University Hospital, Washington, DC, USA
| | - James H Lewis
- Division of Gastroenterology and Hepatology, Georgetown University Hospital, Washington, DC, USA.
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Drug-Induced Steatosis and Steatohepatitis: The Search for Novel Serum Biomarkers Among Potential Biomarkers for Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis. Drug Saf 2020; 42:701-711. [PMID: 30762163 DOI: 10.1007/s40264-018-00790-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Drug-induced steatosis (DIS) and drug-induced steatohepatitis (DISH) are two of several types of drug-induced liver injury (DILI). They can be caused by various drugs and may present as acute, potentially lethal disorders or as chronic slowly progressive liver injury. Despite the fact that they are distinct disorders, the slow progressive forms of DIS and DISH are often confused with or misdiagnosed as non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH), which are much more common and, by definition, not caused by drugs. Currently the only way to identify DIS is via imaging studies or a liver biopsy, while DISH can be identified only through liver biopsy. In addition, diagnosis of either DIS or DISH requires an exhaustive clinical evaluation and comprehensive causality assessment to rule out other possible causes and determine the association with the suspected drug. Furthermore, it is difficult, using existing methods, to monitor the progression of DIS and DISH and to determine the underlying mechanism. Therefore, there is a great unmet need for non-invasive biomarkers that will be able to identify the development of DIS or DISH during drug development and to monitor for progression or regression of the disorder during treatment or following drug discontinuation. Recent developments in the fields of NAFLD and NASH have introduced several novel biomarkers that show promise for the diagnosis, monitoring, and severity assessment of these common diseases. Given the significant overlap in possible underlying mechanisms and histological pattern between NAFLD/NASH and DIS/DISH, these postulated NAFLD and NASH biomarkers may have a potential application to DIS and DISH. This article reviews the existing medical literature and other publically available information pertaining to novel serum biomarkers for NAFLD and NASH, and explores the concurrent identification of these biomarkers for DIS and DISH.
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20
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Evaluation of histophysiological alterations associated with ketoprofen administration in albino NMRI mice. Naunyn Schmiedebergs Arch Pharmacol 2020; 393:1033-1039. [PMID: 31907584 DOI: 10.1007/s00210-019-01806-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Accepted: 12/27/2019] [Indexed: 10/25/2022]
Abstract
The aim of this study was to investigate the changes caused by the administration of ketoprofen to albino NMRI mice on some hematological, biochemical, and structural parameters. For this purpose, the mice were divided into two lots: a control batch and an experimental batch to which ketoprofen was administered subcutaneously at a dose of 10 mg/kg body weight per day for 7 days. A decrease in erythrocyte number and hemoglobin was observed altogether with the increase in white blood cells. Blood biochemistry indicates increased blood glucose, cholesterol, and triglyceride levels. Enzyme values (AST, ALT, and ALP) show a significant increase. Hepatic pathology reveals the enlargement of sinusoidal capillaries, the presence of leukocyte infiltrates associated with necrosis zones.
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21
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Teschke R, Eickhoff A, Brown AC, Neuman MG, Schulze J. Diagnostic Biomarkers in Liver Injury by Drugs, Herbs, and Alcohol: Tricky Dilemma after EMA Correctly and Officially Retracted Letter of Support. Int J Mol Sci 2019; 21:ijms21010212. [PMID: 31892250 PMCID: PMC6981464 DOI: 10.3390/ijms21010212] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 12/21/2019] [Accepted: 12/23/2019] [Indexed: 02/07/2023] Open
Abstract
Liver injuries caused by the use of exogenous compounds such as drugs, herbs, and alcohol are commonly well diagnosed using laboratory tests, toxin analyses, or eventually reactive intermediates generated during metabolic degradation of the respective chemical in the liver and subject to covalent binding by target proteins. Conditions are somewhat different for idiosyncratic drug induced liver injury (DILI), for which metabolic intermediates as diagnostic aids are rarely available. Although the diagnosis of idiosyncratic DILI can well be established using the validated, liver specific, structured, and quantitative RUCAM (Roussel Uclaf Causality Assessment Method), there is an ongoing search for new diagnostic biomarkers that could assist in and also confirm RUCAM-based DILI diagnoses. With respect to idiosyncratic DILI and following previous regulatory letters of recommendations, selected biomarkers reached the clinical focus, including microRNA-122, microRNA-192, cytokeratin analogues, glutamate dehydrogenase, total HMGB-1 (High Mobility Group Box), and hyperacetylated HMGB-1 proteins. However, the new parameters total HMGB-1, and even more so the acetylated HMGB-1, came under critical scientific fire after misconduct at one of the collaborating partner centers, leading the EMA to recommend no longer the exploratory hyperacetylated HMGB1 isoform biomarkers in clinical studies. The overall promising nature of the recommended biomarkers was considered by EMA as highly dependent on the outstanding results of the now incriminated biomarker hyperacetylated HMGB-1. The EMA therefore correctly decided to officially retract its Letter of Support affecting all biomarkers listed above. New biomarkers are now under heavy scrutiny that will require re-evaluations prior to newly adapted recommendations. With Integrin beta 3 (ITGB3), however, a new diagnostic biomarker may emerge, possibly being drug specific but tested in only 16 patients; due to substantial remaining uncertainties, final recommendations would be premature. In conclusion, most of the currently recommended new biomarkers have lost regulatory support due to scientific misconduct, requiring now innovative approaches and re-evaluation before they can be assimilated into clinical practice.
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Affiliation(s)
- Rolf Teschke
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/Main, D-63450 Hanau, Germany;
- Correspondence: ; Tel.: +49-6181-21859; Fax: +49-6181-2964211
| | - Axel Eickhoff
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/Main, D-63450 Hanau, Germany;
| | - Amy C. Brown
- Department of Complementary and Integrative Medicine, University of Hawai’i at Manoa, Honolulu, HI 96813, USA;
| | - Manuela G. Neuman
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M2 R1 W6, Canada;
| | - Johannes Schulze
- Institute of Occupational, Social and Environmental Medicine, Goethe-University Frankfurt/Main, D-60590 Frankfurt/Main, Germany;
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Derakhshanfar A, Moayedi J, Vahedi M, Valizadeh A. Arum conophalloides Aqueous Extract Induced Hepatotoxicity in Rat; Histopathological, Biochemical, and mir-122 Assessments. Microrna 2019; 9:224-231. [PMID: 31622226 PMCID: PMC7366011 DOI: 10.2174/2211536608666191016142400] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Revised: 07/17/2019] [Accepted: 08/07/2019] [Indexed: 11/29/2022]
Abstract
Background Arum conophalloides (A. conophalloides) is a wild edible delicate plant, widely used in traditional medicine. Objective This study aimed to examine the effects of A. conophalloides extracts on biochemical, molecular, and histopathological changes in the rat. Methods Fifty adult male Sprague-Dawley rats were divided into 5 groups (10 each) as follows: G1 or control, received distilled water; G2 and G3, treated with the aqueous extract at doses of 200 and 400 mg/kg; G4 and G5, treated with the hydroalcoholic extract at doses of 200 and 400 mg/kg. Prior to and at the end of the experiments, the serum levels of biochemistry parameters and the relative expression of miR-122 were assessed. Moreover, the liver and kidney tissues were examined microscopically. Results Liver and kidney tissues showed normal structure in all groups. There were no significant changes in biochemical indices or the expression of miR-122 in the extract-treated groups at the dose of 200 mg/kg. However, the group that received the aqueous extract at the dose of 400 mg/kg exhibited a significantly lower level of HDL, LDL, ALT, and ALP in comparison to the control. Additionally, miR-122 expression in this group exhibited a 10-fold increase (P=0.009). Conclusion The serum level of hepatocyte-specific miR-122 will be more helpful in detecting hepatic changes in early stages than ALT and AST activity or histopathological evaluations of liver sections. Our findings highlight the potential hepatotoxicity of A. conophalloides aqueous extract in a rat model.
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Affiliation(s)
- Amin Derakhshanfar
- Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran.,Center of Comparative and Experimental Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Javad Moayedi
- Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran.,Center of Comparative and Experimental Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahjoob Vahedi
- Center of Comparative and Experimental Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abouzar Valizadeh
- Center of Comparative and Experimental Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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Teschke R. Idiosyncratic DILI: Analysis of 46,266 Cases Assessed for Causality by RUCAM and Published From 2014 to Early 2019. Front Pharmacol 2019; 10:730. [PMID: 31396080 PMCID: PMC6664244 DOI: 10.3389/fphar.2019.00730] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 06/05/2019] [Indexed: 12/12/2022] Open
Abstract
One of the most difficult challenges in clinical hepatology is the diagnosis of a drug-induced liver injury (DILI). The timing of the events, exclusion of alternative causes, and taking into account the clinical context should be systematically assessed and scored in a transparent manner. RUCAM (Roussel Uclaf Causality Assessment Method) is a well-established diagnostic algorithm and scale to assess causality in patients with suspected DILI. First published in 1993 and updated in 2016, RUCAM is now the worldwide most commonly used causality assessment method (CAM) for DILI. The following manuscript highlights the recent implementation of RUCAM around the world, by reviewing the literature for publications that utilized RUCAM, and provides a review of “best practices” for the use of RUCAM in cases of suspected DILI. The worldwide appreciation of RUCAM is substantiated by the current analysis of 46,266 DILI cases, all tested for causality using RUCAM. These cases derived from 31 reports published from 2014 to early 2019. Their first authors came from 10 countries, with China on top, followed by the US, and Germany on the third rank. Importantly, all RUCAM-based DILI reports were published in high profile journals. Many other reports were published earlier from 1993 up to 2013 in support of RUCAM. Although most of the studies were of high quality, the current case analysis revealed shortcomings in few studies, not at the level of RUCAM itself but rather associated with the work of the users. To ensure in future DILI cases a better performance by the users, a list of essential elements is proposed. As an example, all suspected DILI cases should be evaluated 1) by the updated RUCAM to facilitate result comparisons, 2) according to a prospective study protocol to ensure complete data sets, 3) after exclusion of cases with herb induced liver injury (HILI) from a DILI cohort to prevent confounding variables, and 4) according to inclusion of DILI cases with RUCAM-based causality gradings of highly probable or probable, in order to increase the specificity of the results. In conclusion, RUCAM benefits from its high appreciation and performs well provided the users adhere to published recommendations to prevent confounding variability.
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Affiliation(s)
- Rolf Teschke
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt, Germany
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Lucena MI, García-Martín E, Daly AK, Blanca M, Andrade RJ, Agúndez JAG. Next-Generation Sequencing of PTGS Genes Reveals an Increased Frequency of Non-synonymous Variants Among Patients With NSAID-Induced Liver Injury. Front Genet 2019; 10:134. [PMID: 30873208 PMCID: PMC6403122 DOI: 10.3389/fgene.2019.00134] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 02/08/2019] [Indexed: 01/03/2023] Open
Abstract
Purpose: The etiopathogenesis of drug-induced liver injury (DILI) is still far from being elucidated. This study aims to the study of genetic variations in DILI, related to the drug target, and specifically in the genes coding for the cyclooxygenase enzymes. Methods: By using Next-generation Sequencing we analyzed the genes coding for COX enzymes (PTGS1 and PTGS2) in 113 individuals, 13 of which were patients with DILI caused by COX-inhibitors. Results: The key findings of the study are the increased frequency, among DILI patients, of SNPs causing alterations in transcription factor binding sites and non-synonymous PTGS gene variants, as compared to control subjects. Moreover, the association with non-synonymous SNPs was exclusive of DILI patients with late-onset (50 days or more) Pc < 0.001 as compared to DILI patients with early onset, or with control subjects. Conclusions: Our findings suggest an interaction of long-term exposure to COX inhibitors combined with functional variants of the COX enzymes in the risk of developing DILI. This is a novel observation that might have been overlooked by previous genetic studies on DILI because of the limited coverage of PTGS genes in exome chips.
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Affiliation(s)
- María Isabel Lucena
- Unidad de Gestión Clínica de Aparato Digestivo, Servicio de Farmacología Clínica, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas Málaga, Instituto de Investigación Biomédica de Málaga, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain
| | - Elena García-Martín
- Instituto de Salud Carlos III, University Institute of Molecular Pathology Biomarkers, UNEx, ARADyAL, Cáceres, Spain
| | - Ann K Daly
- Liver Research Group, Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Miguel Blanca
- Servicio de Alergología, Hospital Infanta Leonor, ARADyAL, Madrid, Spain
| | - Raúl J Andrade
- Unidad de Gestión Clínica de Aparato Digestivo, Servicio de Farmacología Clínica, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas Málaga, Instituto de Investigación Biomédica de Málaga, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain
| | - José A G Agúndez
- Instituto de Salud Carlos III, University Institute of Molecular Pathology Biomarkers, UNEx, ARADyAL, Cáceres, Spain
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Colaci CS, Mendizabal M, Bessone F. Idiosyncratic Drug-Induced Acute Liver Failure: A Challenging and Distressing Scenario. Curr Drug Saf 2019; 14:94-101. [PMID: 30767751 DOI: 10.2174/1574886314666190215115434] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 01/17/2019] [Accepted: 02/09/2019] [Indexed: 01/02/2023]
Abstract
BACKGROUND Idiosyncratic Drug Induced Liver Injury (DILI) is a rare adverse event to drugs that occasionally leads to severe liver damage, being one of the leading causes of Acute Liver Failure (ALF) in developed countries. DILI is largely a diagnosis of exclusion. DISCUSSION AND CONCLUSION Careful history of drug taking and ruling out other competing etiologies is mandatory given that DILI can present with an extremely variable phenotype. Several prognostic scores have been developed to promptly identify patients with potential risk of developing ALF. New biomarkers to diagnose and predict DILI evolution are under study and hopefully we will benefit from these novel tools in the near future.
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Affiliation(s)
- Carla Stefania Colaci
- Hepatology and Liver Transplant Unit, Hospital Universitario Austral, Pilar, Buenos Aires, Argentina
| | - Manuel Mendizabal
- Hepatology and Liver Transplant Unit, Hospital Universitario Austral, Pilar, Buenos Aires, Argentina
- Latin American Liver Research Educational and Awareness Network (LALREAN), Pilar, Buenos Aires, Argentina
| | - Fernando Bessone
- Hospital Provincial del Centenario, University of Rosario School of Medicine, Rosario, Santa Fe, Argentina
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26
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Cole LM, Clench MR, Francese S. Sample Treatment for Tissue Proteomics in Cancer, Toxicology, and Forensics. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1073:77-123. [PMID: 31236840 DOI: 10.1007/978-3-030-12298-0_4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Since the birth of proteomics science in the 1990, the number of applications and of sample preparation methods has grown exponentially, making a huge contribution to the knowledge in life science disciplines. Continuous improvements in the sample treatment strategies unlock and reveal the fine details of disease mechanisms, drug potency, and toxicity as well as enable new disciplines to be investigated such as forensic science.This chapter will cover the most recent developments in sample preparation strategies for tissue proteomics in three areas, namely, cancer, toxicology, and forensics, thus also demonstrating breath of application within the domain of health and well-being, pharmaceuticals, and secure societies.In particular, in the area of cancer (human tumor biomarkers), the most efficient and multi-informative proteomic strategies will be covered in relation to the subsequent application of matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) and liquid extraction surface analysis (LESA), due to their ability to provide molecular localization of tumor biomarkers albeit with different spatial resolution.With respect to toxicology, methodologies applied in toxicoproteomics will be illustrated with examples from its use in two important areas: the study of drug-induced liver injury (DILI) and studies of effects of chemical and environmental insults on skin, i.e., the effects of irritants, sensitizers, and ionizing radiation. Within this chapter, mainly tissue proteomics sample preparation methods for LC-MS/MS analysis will be discussed as (i) the use of LC-MS/MS is majorly represented in the research efforts of the bioanalytical community in this area and (ii) LC-MS/MS still is the gold standard for quantification studies.Finally, the use of proteomics will also be discussed in forensic science with respect to the information that can be recovered from blood and fingerprint evidence which are commonly encountered at the scene of the crime. The application of proteomic strategies for the analysis of blood and fingerprints is novel and proteomic preparation methods will be reported in relation to the subsequent use of mass spectrometry without any hyphenation. While generally yielding more information, hyphenated methods are often more laborious and time-consuming; since forensic investigations need quick turnaround, without compromising validity of the information, the prospect to develop methods for the application of quick forensic mass spectrometry techniques such as MALDI-MS (in imaging or profiling mode) is of great interest.
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Affiliation(s)
- L M Cole
- Biomolecular Science Research Centre, Centre for Mass Spectrometry Imaging, Sheffield Hallam University, Sheffield, UK
| | - M R Clench
- Biomolecular Science Research Centre, Centre for Mass Spectrometry Imaging, Sheffield Hallam University, Sheffield, UK
| | - S Francese
- Biomolecular Science Research Centre, Centre for Mass Spectrometry Imaging, Sheffield Hallam University, Sheffield, UK.
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Teschke R. Idiosyncratic DILI: Analysis of 46,266 Cases Assessed for Causality by RUCAM and Published From 2014 to Early 2019. Front Pharmacol 2019. [PMID: 31396080 DOI: 10.389/fphar.2019.00730] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/07/2023] Open
Abstract
One of the most difficult challenges in clinical hepatology is the diagnosis of a drug-induced liver injury (DILI). The timing of the events, exclusion of alternative causes, and taking into account the clinical context should be systematically assessed and scored in a transparent manner. RUCAM (Roussel Uclaf Causality Assessment Method) is a well-established diagnostic algorithm and scale to assess causality in patients with suspected DILI. First published in 1993 and updated in 2016, RUCAM is now the worldwide most commonly used causality assessment method (CAM) for DILI. The following manuscript highlights the recent implementation of RUCAM around the world, by reviewing the literature for publications that utilized RUCAM, and provides a review of "best practices" for the use of RUCAM in cases of suspected DILI. The worldwide appreciation of RUCAM is substantiated by the current analysis of 46,266 DILI cases, all tested for causality using RUCAM. These cases derived from 31 reports published from 2014 to early 2019. Their first authors came from 10 countries, with China on top, followed by the US, and Germany on the third rank. Importantly, all RUCAM-based DILI reports were published in high profile journals. Many other reports were published earlier from 1993 up to 2013 in support of RUCAM. Although most of the studies were of high quality, the current case analysis revealed shortcomings in few studies, not at the level of RUCAM itself but rather associated with the work of the users. To ensure in future DILI cases a better performance by the users, a list of essential elements is proposed. As an example, all suspected DILI cases should be evaluated 1) by the updated RUCAM to facilitate result comparisons, 2) according to a prospective study protocol to ensure complete data sets, 3) after exclusion of cases with herb induced liver injury (HILI) from a DILI cohort to prevent confounding variables, and 4) according to inclusion of DILI cases with RUCAM-based causality gradings of highly probable or probable, in order to increase the specificity of the results. In conclusion, RUCAM benefits from its high appreciation and performs well provided the users adhere to published recommendations to prevent confounding variability.
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Affiliation(s)
- Rolf Teschke
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt, Germany
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Liu Y, Li P, Liu L, Zhang Y. The diagnostic role of miR-122 in drug-induced liver injury: A systematic review and meta-analysis. Medicine (Baltimore) 2018; 97:e13478. [PMID: 30544438 PMCID: PMC6310488 DOI: 10.1097/md.0000000000013478] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2018] [Accepted: 11/07/2018] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Drug-induced liver injury (DILI) is a potentially severe adverse drug reaction especially in susceptible patients. But there are no sensitive or specific parameters to detecting DILI. The specific expression of miR-122 in the liver has been a hotspot in the evaluation of hepatic toxicity due to its high stability and sensitivity. METHODS We performed a systematic literature review through July 31, 2017 to identify studies which evolved DILI patients testing miR-122 without limiting a certain drug. According to the PRISMA statement, a meta-analysis: the diagnostic role of miR-122 in DILI was made. QUADAS-2 quality evaluation table was used to evaluate the quality of the documentary evidence, PRISMA flowchart and quality evaluation table were drawn with RevMan, use Stata to calculate the sensitivity and specificity of miR-122 in diagnosing DILI, ROC curve and Deeks funnel plot were also drawn by STATA. RESULTS Eleven studies involved 194 DILI patients and 251 controls, all were tested miR-122 (fold change). Sensitivity of miR-122 in diagnosing DILI was [0.85 (95% CI, 0.75-0.91), I = 53.46%] and specificity was [0.93 (95% CI, 0.86-0.97), I = 65.10%], the area under ROC curve was 0.95 (95% CI, 0.93-0.97). While in acetaminophen (APAP)-induced liver injury, the sensitivity was [0.82 (95%CI, 0.67-0.91), I = 65.77%] specificity was [0.96 (95%CI, 0.88-0.99), I = 31.46%], AUROC was 0.97 (95% CI, 0.95-0.98). CONCLUSIONS In this systematic review and meta-analysis, we found miR-122 have a high specificity in DILI, and a modest positive diagnostic effects. On the basis of the limited evidence, further research is needed to evaluate the long-term observation and more clinical data to testify miR-122 in diagnosing DILI.
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Affiliation(s)
- Yiqi Liu
- School of Graduates, Tianjin Medical University
- Department of Hepatology, Tianjin Second People's Hospital
| | - Ping Li
- Department of Hepatology, Tianjin Second People's Hospital
- Tianjin Research Institute of Liver Diseases, Tianjin, China
| | - Liang Liu
- School of Graduates, Tianjin Medical University
- Department of Hepatology, Tianjin Second People's Hospital
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Vincenzi B, Russo A, Terenzio A, Galvano A, Santini D, Vorini F, Antonelli-Incalzi R, Vespasiani-Gentilucci U, Tonini G. The use of SAMe in chemotherapy-induced liver injury. Crit Rev Oncol Hematol 2018; 130:70-77. [PMID: 30196914 DOI: 10.1016/j.critrevonc.2018.06.019] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2018] [Revised: 06/22/2018] [Accepted: 06/25/2018] [Indexed: 02/07/2023] Open
Abstract
Drug-induced liver injury (DILI) remains the most common cause of acute liver failure in the Western world. Chemotherapy is one of the major class of drugs most frequently associated with idiosyncratic DILI. For this reason, patients who receive chemotherapy require careful assessment of liver function prior to treatment to determine which drugs may not be appropriate and which drug doses should be modified. S-adenosylmethionine (SAMe) is an endogenous agent derived from methionine. Its supplementation is effective in the treatment of liver disease, in particular intrahepatic cholestasis (IHC). The target of this review is to analyze the mechanisms of hepatotoxicity of the principal anticancer agents and the role of SAMe in the prevention of this complication.
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Affiliation(s)
- B Vincenzi
- Medical Oncology Unit, Campus Bio-Medico University, Rome, Italy.
| | - A Russo
- Department of Surgery and Oncology, Section of Medical Oncology, University of Palermo, Italy
| | - A Terenzio
- Medical Oncology Unit, Campus Bio-Medico University, Rome, Italy
| | - A Galvano
- Department of Surgery and Oncology, Section of Medical Oncology, University of Palermo, Italy
| | - D Santini
- Medical Oncology Unit, Campus Bio-Medico University, Rome, Italy
| | - F Vorini
- Interdisciplinary Center for Biomedical Research (CIR), Laboratory of Internal Medicine and Hepatology, Campus Bio-Medico University, Rome, Italy
| | | | - U Vespasiani-Gentilucci
- Interdisciplinary Center for Biomedical Research (CIR), Laboratory of Internal Medicine and Hepatology, Campus Bio-Medico University, Rome, Italy
| | - G Tonini
- Medical Oncology Unit, Campus Bio-Medico University, Rome, Italy
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Barnhill MS, Real M, Lewis JH. Latest advances in diagnosing and predicting DILI: what was new in 2017? Expert Rev Gastroenterol Hepatol 2018; 12:1033-1043. [PMID: 30111182 DOI: 10.1080/17474124.2018.1512854] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Drug-induced liver injury (DILI) remains an increasingly recognized cause of hepatotoxicity and liver failure worldwide. In 2017, we continued to learn about predicting, diagnosing, and prognosticating drug hepatotoxicity. Areas covered: In this review, we selected from over 1200 articles from 2017 to synopsize updates in DILI. There were new HLA haplotypes associated with medications including HLA-C0401 and HLA-B*14. There has been continued work with quantitative systems pharmacology, particularly with the DILIsym® initiative, which employs mathematical representations of DILI mechanisms to predict hepatotoxicity in simulated populations. Additionally, knowledge regarding microRNAs (miRNAs) continues to expand. Some new miRNAs this past year include miRNA-223 and miRNA-605. Aside from miRNAs, other biomarkers for diagnosis, prognosis, and even prediction of DILI were explored. Studies on K18, OPN, and MCSFR have correlated DILI and liver-associated death within 6 months. Conversely, a new prognostic panel using apolipoportein-A1 and haptoglobin has been proposed to predict recovery. Further study of CDH5 has also provided researchers a possible new biomarker for prediction and susceptibility to DILI. Expert commentary: Although research on DILI remains quite promising, there is yet to be a reliable, simple method to predict, diagnose, and risk assess this form of hepatotoxicity.
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Affiliation(s)
- Michele S Barnhill
- a Department of Internal Medicine , Medstar Georgetown University Hospital , Washington , DC , USA
| | - Mark Real
- a Department of Internal Medicine , Medstar Georgetown University Hospital , Washington , DC , USA
| | - James H Lewis
- b Department of Gastroenterology , Medstar Georgetown University Hospital , Washington , DC , USA
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31
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Kammerer S, Küpper JH. Human hepatocyte systems for in vitro toxicology analysis. ACTA ACUST UNITED AC 2018. [DOI: 10.3233/jcb-179012] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Sarah Kammerer
- Institute of Biotechnology, Brandenburg University of Technology, Cottbus-Senftenberg, Germany
| | - Jan-Heiner Küpper
- Institute of Biotechnology, Brandenburg University of Technology, Cottbus-Senftenberg, Germany
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Benesic A, Rotter I, Dragoi D, Weber S, Leitl A, Buchholtz ML, Gerbes AL. Development and Validation of a Test to Identify Drugs That Cause Idiosyncratic Drug-Induced Liver Injury. Clin Gastroenterol Hepatol 2018; 16:1488-1494.e5. [PMID: 29723689 DOI: 10.1016/j.cgh.2018.04.049] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Revised: 04/08/2018] [Accepted: 04/20/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Idiosyncratic drug-induced liver injury (iDILI) is one of the most challenging diagnoses in hepatology. It is frequently impossible to identify the agent that has caused iDILI in patients who take multiple medicines. We developed an in vitro method to identify drugs that cause liver injury in patients, based on drug toxicity to monocyte-derived hepatocyte-like (MH) cells from patient blood samples. We then collected data on patients who were re-exposed to drugs found to be toxic in the MH test to validate test performance. METHODS We performed a prospective study of patients referred to the University Hospital in Munich, Germany, with acute liver injury believed to be caused by medications (300 patients were enrolled in the study and we present data from 40 patients with iDILI and re-exposure to implicated drugs). We collected data from patients on medical history, laboratory test and imaging results, findings from biopsy analyses, and medications taken. Blood samples were collected from all patients and MH cells were isolated and cultured for 10 days. MH cells were then incubated with drugs to which each patient had been exposed, and toxicity was measured based on release of lactate dehydrogenase. Agents found to be toxic to MH cells were considered as candidates for the cause of liver injury. Patients were followed up for up to 6 months after liver injury and data on drug re-exposures and subsequent liver damage within the following 3 to 24 months were associated with findings from MH tests. RESULTS Our test identified 10 drugs that were toxic to MH cells from 13 patients (amoxicillin/clavulanate to cells from 2 patients; diclofenac to cells from 2 patients; methylprednisolone to cells from 2 patients; and atorvastatin, metamizole, pembrolizumab, piperacillin/tazobactam, moxifloxacin, duloxetine, or sertraline each to cells from 1 patient). Thirteen patients had a recurrence of liver injury after inadvertent re-exposure to a single drug, and the MH test correctly identified 12 of the 13 drugs that caused these liver re-injury events. All 86 drugs that were not toxic to MH cells in our assay were safely resumed by patients and were not associated with liver re-injury in 27 patients. Therefore, the MH test identifies drugs that cause liver injury with 92.3% sensitivity and 100% specificity (1 false-negative and 12 true-positive results). CONCLUSIONS We developed a test to identify drugs that cause liver injury in patients based on their toxicity to MH cells isolated from patients with DILI. We validated results from the assay and found it to identify drugs that cause DILI with 92.3% sensitivity and 100% specificity. The MH cell test could be a tool to identify causes of iDILI, even in patients taking multiple medications. ClinicalTrials.gov no: NCT 02353455.
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Affiliation(s)
- Andreas Benesic
- Department of Internal Medicine 2, Liver Centre Munich, University Hospital Munich (Klinikum der Universität München), Campus Großhadern, Ludwig-Maximilians-Universität Munich, Germany; MetaHeps GmbH, Martinsried, Germany.
| | - Isabelle Rotter
- Department of Internal Medicine 2, Liver Centre Munich, University Hospital Munich (Klinikum der Universität München), Campus Großhadern, Ludwig-Maximilians-Universität Munich, Germany
| | - Diana Dragoi
- Department of Internal Medicine 2, Liver Centre Munich, University Hospital Munich (Klinikum der Universität München), Campus Großhadern, Ludwig-Maximilians-Universität Munich, Germany; MetaHeps GmbH, Martinsried, Germany
| | - Sabine Weber
- Department of Internal Medicine 2, Liver Centre Munich, University Hospital Munich (Klinikum der Universität München), Campus Großhadern, Ludwig-Maximilians-Universität Munich, Germany
| | | | - Marie-Luise Buchholtz
- Department of Internal Medicine 2, Liver Centre Munich, University Hospital Munich (Klinikum der Universität München), Campus Großhadern, Ludwig-Maximilians-Universität Munich, Germany; Institute of Laboratory Medicine, University Hospital, Ludwig-Maximilians-Universität Munich, Germany
| | - Alexander L Gerbes
- Department of Internal Medicine 2, Liver Centre Munich, University Hospital Munich (Klinikum der Universität München), Campus Großhadern, Ludwig-Maximilians-Universität Munich, Germany
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Trends in reporting drug-associated liver injuries in Taiwan: a focus on amiodarone. Int J Clin Pharm 2018; 40:911-920. [PMID: 30051228 DOI: 10.1007/s11096-018-0698-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2017] [Accepted: 07/20/2018] [Indexed: 12/18/2022]
Abstract
Background A pharmacovigilance database of real-world adverse drug reaction (ADR) reports is helpful for characterising adverse events and identifying new signals after drug approval. Objective This study aimed to analyse trends of ADR reporting in relation to liver injury and to delineate critical factors for suspected drug-related hepatotoxicity with a focus on reports associated with amiodarone. Setting The 2000-2014 Taiwan pharmacovigilance database. Method Relevant Standardized Medical Dictionary for Regulatory Activities queries were used to identify reports associated with liver injury. Information on ADR, patient characteristics, and the verbatim pertaining to amiodarone prescriptions, liver injury, comedications, and comorbidities were extracted and evaluated. Group comparisons between Hy's Law cases and Temple's Corollary cases of suspected amiodarone-related hepatotoxicity were performed. Main outcome measure Number and nature of drug-related liver injuries, particularly those associated with amiodarone. Results Of the 98,777 ADR reports over a 15-year period, 4261 (4.3%) were related to liver injury. Sixty-eight reports contained amiodarone prescriptions, but only 49 (1.1%) were eligible for further analysis. Hepatotoxic cases associated with amiodarone mostly occurred within 1 week, exhibited a hepatocellular pattern, and were more common among elderly individuals. Among 23 discernible cases, four (17.4%) recovered fully from liver injury. The critical Hy's Law cases were associated with shorter height, lower body surface area, and higher average daily doses. Conclusion This study substantiates the importance of ADR reporting. Data pertaining to drug-associated liver injury and factors associated with suspected amiodarone-related hepatotoxicity warrants continual attention in pharmacovigilance for those at risk, especially the elderly.
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Dragoi D, Benesic A, Pichler G, Kulak NA, Bartsch HS, Gerbes AL. Proteomics Analysis of Monocyte-Derived Hepatocyte-Like Cells Identifies Integrin Beta 3 as a Specific Biomarker for Drug-Induced Liver Injury by Diclofenac. Front Pharmacol 2018; 9:699. [PMID: 30022949 PMCID: PMC6039575 DOI: 10.3389/fphar.2018.00699] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 06/08/2018] [Indexed: 12/12/2022] Open
Abstract
Idiosyncratic drug-induced liver injury (iDILI) is a major cause of acute liver failure resulting in liver transplantation or death. Prediction and diagnosis of iDILI remain a great challenge, as current models provide unsatisfying results in terms of sensitivity, specificity, and prognostic value. The absence of appropriate tools for iDILI detection also impairs the development of reliable biomarkers. Here, we report on a new method for identification of drug-specific biomarkers. We combined the advantages of monocyte-derived hepatocyte-like (MH) cells, able to mimic individual characteristics, with those of a novel mass spectrometry-based proteomics technology to assess potential biomarkers for Diclofenac-induced DILI. We found over 2,700 proteins differentially regulated in MH cells derived from individual patients. Herefrom, we identified integrin beta 3 (ITGB3) to be specifically upregulated in Diclofenac-treated MH cells from Diclofenac-DILI patients compared to control groups. Finally, we validated ITGB3 by flow cytometry analysis of whole blood and histological staining of liver biopsies derived from patients diagnosed with Diclofenac-DILI. In summary, our results show that biomarker candidates can be identified by proteomics analysis of MH cells. Application of this method to a broader range of drugs in the future will exploit its full potential for the development of drug-specific biomarkers. Data are available via ProteomeXchange with identifier PXD008918.
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Affiliation(s)
- Diana Dragoi
- Department of Medicine 2, Liver Centre Munich, University Hospital Munich, Munich, Germany.,MetaHeps GmbH, Martinsried, Germany
| | - Andreas Benesic
- Department of Medicine 2, Liver Centre Munich, University Hospital Munich, Munich, Germany.,MetaHeps GmbH, Martinsried, Germany
| | - Garwin Pichler
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany.,PreOmics GmbH, Martinsried, Germany
| | - Nils A Kulak
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany.,PreOmics GmbH, Martinsried, Germany
| | - Harald S Bartsch
- Institute of Pathology, Medical School, Ludwig Maximilian University, Munich, Germany
| | - Alexander L Gerbes
- Department of Medicine 2, Liver Centre Munich, University Hospital Munich, Munich, Germany
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Rahmel T, Rump K, Adamzik M, Peters J, Frey UH. Increased circulating microRNA-122 is associated with mortality and acute liver injury in the acute respiratory distress syndrome. BMC Anesthesiol 2018; 18:75. [PMID: 29935532 PMCID: PMC6015662 DOI: 10.1186/s12871-018-0541-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Accepted: 06/06/2018] [Indexed: 12/11/2022] Open
Abstract
Background Acute liver injury in patients with ARDS decreases survival but early stages may be easily missed due to the lack of sufficient biomarkers signalling its onset. Accordingly, we tested in ARDS patients the hypotheses that microRNA-122, the foremost liver-related microRNA (miR), 1) is an sensitive and specific early predictor for potential liver injury and 2) analysed its impact on 30-day-survival. Methods We collected clinical data and analysed blood samples from 119 ARDS patients within the first 24 h of ICU admission and from 20 patients undergoing elective abdominal non-liver surgery serving as controls. Total circulating miR was isolated from serum and relative miR-122 expression was measured (using specific probes and spiked-in miR-54), as were liver function and 30-day survival. Acute liver injury was defined as a total bilirubin concentration ≥ 3.0 mg/dl, an ALT activity ≥350 U/l, and an INR ≥2.0. Results 30-day survival of the entire ARDS-cohort was 69% but differed between patients with normal liver function (77%) and acute liver injury (19% p < 0.001). miR-122 expression was 20fold higher in non-survivors (95%-CI 0.0149–0.0768; p = 0.001) and almost 4fold greater in survivors (95%-CI: 0.0037–0.0122; p = 0.005) compared to controls (95%-CI 0.0008–0.0034) and correlated with markers of liver cell integrity/function [ALT (p < 0.001, r = 0.495), AST (p < 0.001, r = 0.537), total bilirubin (p = 0.025, r = 0.206), INR (p = 0.001, r = 0.308), and GLDH (p < 0.001, r = 0.489)]. miR-122 serum expression discriminated survivors and non-survivors (AUC: 0.78) better than total bilirubin concentration (AUC: 0.66). Multivariable Cox-regression analysis revealed both acute liver injury (HR 7.6, 95%-CI 2.9–19.8, p < 0.001) and miR-122 (HR 4.4, 95%-CI 1.2–16.1, p = 0.02) as independent prognostic factors for 30-day mortality. Conclusions Increased miR-122 serum expression is an early and independent risk factor for 30-day mortality in ARDS patients and potentially reveal an acute liver injury earlier than the conventional markers of liver cell integrity. Electronic supplementary material The online version of this article (10.1186/s12871-018-0541-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Tim Rahmel
- Klinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Universitätsklinikum Knappschaftskrankenhaus Bochum, In der Schornau 23-25, D-44892, Bochum, Germany.
| | - Katharina Rump
- Klinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Universitätsklinikum Knappschaftskrankenhaus Bochum, In der Schornau 23-25, D-44892, Bochum, Germany
| | - Michael Adamzik
- Klinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Universitätsklinikum Knappschaftskrankenhaus Bochum, In der Schornau 23-25, D-44892, Bochum, Germany.,Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen & Universitätsklinikum Essen, D-45122, Essen, Germany
| | - Jürgen Peters
- Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen & Universitätsklinikum Essen, D-45122, Essen, Germany
| | - Ulrich H Frey
- Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen & Universitätsklinikum Essen, D-45122, Essen, Germany
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Schueller F, Roy S, Vucur M, Trautwein C, Luedde T, Roderburg C. The Role of miRNAs in the Pathophysiology of Liver Diseases and Toxicity. Int J Mol Sci 2018; 19:ijms19010261. [PMID: 29337905 PMCID: PMC5796207 DOI: 10.3390/ijms19010261] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 01/12/2018] [Accepted: 01/13/2018] [Indexed: 12/12/2022] Open
Abstract
Both acute and chronic liver toxicity represents a major global health burden and an important cause of morbidity and lethality worldwide. Despite epochal progress in the treatment of hepatitis C virus infections, pharmacological treatment strategies for most liver diseases are still limited and new targets for prevention or treatment of liver disease are urgently needed. MicroRNAs (miRNAs) represent a new class of highly conserved small non-coding RNAs that are involved in the regulation of gene expression by targeting whole networks of so called “targets”. Previous studies have shown that the expression of miRNAs is specifically altered in almost all acute and chronic liver diseases. In this context, it was shown that miRNA can exert causal roles, being pro- or anti-inflammatory, as well as pro- or antifibrotic mediators or being oncogenes as well as tumor suppressor genes. Recent data suggested a potential therapeutic use of miRNAs by targeting different steps in the hepatic pathophysiology. Here, we review the function of miRNAs in the context of acute and chronic liver diseases. Furthermore, we highlight the potential role of circulating microRNAs in diagnosis of liver diseases and discuss the major challenges and drawbacks that currently prevent the use of miRNAs in clinical routine.
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Affiliation(s)
- Florian Schueller
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
| | - Sanchari Roy
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
| | - Mihael Vucur
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
| | - Christian Trautwein
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
| | - Tom Luedde
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
- Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
| | - Christoph Roderburg
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
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Howell LS, Ireland L, Park BK, Goldring CE. MiR-122 and other microRNAs as potential circulating biomarkers of drug-induced liver injury. Expert Rev Mol Diagn 2017; 18:47-54. [PMID: 29235390 DOI: 10.1080/14737159.2018.1415145] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Drug-induced liver injury (DILI) is a severe adverse drug reaction which is of major concern to patients, clinicians and the pharmaceutical industry. Accurate and rapid detection of DILI is important for patient stratification and treatment in the clinic and benefits preclinical drug design and risk assessment. MicroRNAs (miRNAs) offer a potential new and improved class of circulating biomarkers of DILI over the current gold standard biomarkers. Areas covered: This review highlights the shortcomings of the currently used panel of biomarkers and how miRNAs, primarily miR-122, show an improved level of specificity and sensitivity in the prediction of DILI. Furthermore, the use of miRNAs as potential markers of progression of DILI and specific zonated damage within the liver is discussed. Expert commentary: MiRNAs offer more sensitive and specific markers over the current biomarkers for DILI. Combinations of different miRNAs may be able to relay the location of DILI and the progression of disease. More studies using different hepatotoxins apart from acetaminophen will ultimately strengthen the case for the clinical introduction of miRNAs as biomarkers of DILI.
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Affiliation(s)
- Lawrence S Howell
- a MRC Centre for Drug Safety Science , University of Liverpool , Liverpool , UK
| | - Lucy Ireland
- b Department of Molecular and Clinical Cancer Medicine , University of Liverpool , Liverpool , UK
| | - B Kevin Park
- a MRC Centre for Drug Safety Science , University of Liverpool , Liverpool , UK
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Lundgren H, Martinsson K, Cederbrant K, Jirholt J, Mucs D, Madeyski-Bengtson K, Havarinasab S, Hultman P. HLA-DR7 and HLA-DQ2: Transgenic mouse strains tested as a model system for ximelagatran hepatotoxicity. PLoS One 2017; 12:e0184744. [PMID: 28934241 PMCID: PMC5608249 DOI: 10.1371/journal.pone.0184744] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Accepted: 08/30/2017] [Indexed: 01/11/2023] Open
Abstract
The oral thrombin inhibitor ximelagatran was withdrawn in the late clinical trial phase because it adversely affected the liver. In approximately 8% of treated patients, drug-induced liver injury (DILI) was expressed as transient alanine transaminase (ALT) elevations. No evidence of DILI had been revealed in the pre-clinical in vivo studies. A whole genome scan study performed on the clinical study material identified a strong genetic association between the major histocompatibility complex alleles for human leucocyte antigens (HLA) (HLA-DR7 and HLA-DQ2) and elevated ALT levels in treated patients. An immune-mediated pathogenesis was suggested. Here, we evaluated whether HLA transgenic mice models could be used to investigate whether the expression of relevant HLA molecules was enough to reproduce the DILI effects in humans. In silico modelling performed in this study revealed association of both ximelagatran (pro-drug) and melagatran (active drug) to the antigen-presenting groove of the homology modelled HLA-DR7 molecule suggesting “altered repertoire” as a key initiating event driving development of DILI in humans. Transgenic mouse strains (tgms) expressing HLA of serotype HLA-DR7 (HLA-DRB1*0701, -DRA*0102), and HLA-DQ2 (HLA-DQB1*0202,–DQA1*0201) were created. These two lines were crossed with a human (h)CD4 transgenic line, generating the two tgms DR7xhCD4 and DQ2xhCD4. To investigate whether the DILI effects observed in humans could be reproduced in tgms, the mice were treated for 28 days with ximelagatran. Results revealed no signs of DILI when biomarkers for liver toxicity were measured and histopathology was evaluated. In the ximelagatran case, presence of relevant HLA-expression in a pre-clinical model did not fulfil the prerequisite for reproducing DILI observed in patients. Nonetheless, for the first time an HLA-transgenic mouse model has been investigated for use in HLA-associated DILI induced by a low molecular weight compound. This study shows that mimicking of genetic susceptibility, expressed as DILI-associated HLA-types in mice, is not sufficient for reproducing the complex pathogenesis leading to DILI in man.
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Affiliation(s)
- Hanna Lundgren
- Division of Molecular and Immunological Pathology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Östergötland County Council, Linköping, Sweden
| | - Klara Martinsson
- AIR/Rheumatology Unit, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Östergötland County Council, Linköping, Sweden
| | - Karin Cederbrant
- Division of Molecular and Immunological Pathology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Östergötland County Council, Linköping, Sweden
- Swetox, Karolinska Institutet, Unit of Toxicology Sciences, Södertälje, Sweden
- * E-mail:
| | | | - Daniel Mucs
- Swetox, Karolinska Institutet, Unit of Toxicology Sciences, Södertälje, Sweden
| | | | - Said Havarinasab
- Division of Molecular and Immunological Pathology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Östergötland County Council, Linköping, Sweden
| | - Per Hultman
- Division of Molecular and Immunological Pathology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Östergötland County Council, Linköping, Sweden
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Araújo AM, Carvalho M, Carvalho F, Bastos MDL, Guedes de Pinho P. Metabolomic approaches in the discovery of potential urinary biomarkers of drug-induced liver injury (DILI). Crit Rev Toxicol 2017; 47:633-649. [PMID: 28436314 DOI: 10.1080/10408444.2017.1309638] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Drug-induced liver injury (DILI) is a major safety issue during drug development, as well as the most common cause for the withdrawal of drugs from the pharmaceutical market. The identification of DILI biomarkers is a labor-intensive area. Conventional biomarkers are not specific and often only appear at significant levels when liver damage is substantial. Therefore, new biomarkers for early identification of hepatotoxicity during the drug discovery process are needed, thus resulting in lower development costs and safer drugs. In this sense, metabolomics has been increasingly playing an important role in the discovery of biomarkers of liver damage, although the characterization of the mechanisms of toxicity induced by xenobiotics remains a huge challenge. These new-generation biomarkers will offer obvious benefits for the pharmaceutical industry, regulatory agencies, as well as a personalized clinical follow-up of patients, upon validation and translation into clinical practice or approval for routine use. This review describes the current status of the metabolomics applied to the early diagnosis and prognosis of DILI and in the discovery of new potential urinary biomarkers of liver injury.
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Affiliation(s)
- Ana Margarida Araújo
- a UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy , University of Porto , Porto , Portugal
| | - Márcia Carvalho
- a UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy , University of Porto , Porto , Portugal
- b UFP Energy, Environment and Health Research Unit (FP-ENAS) , University Fernando Pessoa , Porto , Portugal
| | - Félix Carvalho
- a UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy , University of Porto , Porto , Portugal
| | - Maria de Lourdes Bastos
- a UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy , University of Porto , Porto , Portugal
| | - Paula Guedes de Pinho
- a UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy , University of Porto , Porto , Portugal
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Clare KE, Miller MH, Dillon JF. Genetic Factors Influencing Drug-Induced Liver Injury: Do They Have a Role in Prevention and Diagnosis? ACTA ACUST UNITED AC 2017; 16:258-264. [PMID: 28856081 PMCID: PMC5556130 DOI: 10.1007/s11901-017-0363-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Purpose of Review The pathogenesis of DILI is currently unknown; however, research has shown strong genetic associations with some DILIs. This paper describes the variant alleles uncovered by GWAS and discusses their potential role as susceptibility biomarkers. Recent Findings An association with HLADRB1*15:01 and amoxicillin/clavulanate DILI has been shown by a number of research groups. The presence of the HLA-B*57:01 allele has been associated with an 81-fold increased risk of flucloxacillin DILI. The HLA-B*35:02 allele has significant association with minocycline DILI. Summary With the exception of abacavir for HIV therapy, no other prospective genetic screening tests have met the threshold for clinical application. This is largely because DILI incidence is too low to warrant the cost and effort associated with testing. Perhaps, with the development of personalised medicine, a panel of genes for disease susceptibility, drug efficacy and adverse reactions could be tested once off. This would change the cost-effectiveness paradigm, personalise healthcare and reduce DILI risk by avoiding medications in patients with specific HLA alleles.
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Affiliation(s)
- Kathleen E Clare
- The GUT Group, Division of Molecular and Clinical Medicine, School of Medicine, Ninewells Hospital and Medical School, University of Dundee, James Arnott Drive, Dundee, DD1 9SY UK
| | - Michael H Miller
- The GUT Group, Division of Molecular and Clinical Medicine, School of Medicine, Ninewells Hospital and Medical School, University of Dundee, James Arnott Drive, Dundee, DD1 9SY UK
| | - John F Dillon
- The GUT Group, Division of Molecular and Clinical Medicine, School of Medicine, Ninewells Hospital and Medical School, University of Dundee, James Arnott Drive, Dundee, DD1 9SY UK
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Weaver RJ, Betts C, Blomme EAG, Gerets HHJ, Gjervig Jensen K, Hewitt PG, Juhila S, Labbe G, Liguori MJ, Mesens N, Ogese MO, Persson M, Snoeys J, Stevens JL, Walker T, Park BK. Test systems in drug discovery for hazard identification and risk assessment of human drug-induced liver injury. Expert Opin Drug Metab Toxicol 2017; 13:767-782. [PMID: 28604124 DOI: 10.1080/17425255.2017.1341489] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION The liver is an important target for drug-induced toxicities. Early detection of hepatotoxic drugs requires use of well-characterized test systems, yet current knowledge, gaps and limitations of tests employed remains an important issue for drug development. Areas Covered: The current state of the science, understanding and application of test systems in use for the detection of drug-induced cytotoxicity, mitochondrial toxicity, cholestasis and inflammation is summarized. The test systems highlighted herein cover mostly in vitro and some in vivo models and endpoint measurements used in the assessment of small molecule toxic liabilities. Opportunities for research efforts in areas necessitating the development of specific tests and improved mechanistic understanding are highlighted. Expert Opinion: Use of in vitro test systems for safety optimization will remain a core activity in drug discovery. Substantial inroads have been made with a number of assays established for human Drug-induced Liver Injury. There nevertheless remain significant gaps with a need for improved in vitro tools and novel tests to address specific mechanisms of human Drug-Induced Liver Injury. Progress in these areas will necessitate not only models fit for application, but also mechanistic understanding of how chemical insult on the liver occurs in order to identify translational and quantifiable readouts for decision-making.
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Affiliation(s)
- Richard J Weaver
- a Research & Biopharmacy, Institut de Recherches Internationales Servier , Suresnes , France
| | - Catherine Betts
- b Pathology Sciences, Drug Safety and Metabolism , AstraZeneca R&D , Cambridge , UK
| | | | - Helga H J Gerets
- d Non Clinical Development, Chemin du Foriest , UCB BioPharma SPRL , Braine L'Alleud , Belgium
| | | | - Philip G Hewitt
- f Non-Clinical Development, Merck KGaA , Darmstadt , Germany
| | - Satu Juhila
- g In Vitro Biology , Orion Pharma , Espoo , Finland
| | - Gilles Labbe
- h Investigative Toxicology, Preclinical Safety , Sanofi R&D , Paris , France
| | | | - Natalie Mesens
- i Preclinical Development & Safety, Janssen (Pharmaceutical Companies of Johnson & Johnson) Turnhoutseweg 30 , Beerse , Belgium
| | - Monday O Ogese
- j Pathology Sciences, Drug Safety and Metabolism , AstraZeneca R&D , Cambridge , UK
| | - Mikael Persson
- k Innovative Medicines and Early Clinical Development, Drug Safety and Metabolism, Discovery Safety , AstraZeneca R&D , Mölndal , Sweden
| | - Jan Snoeys
- l Pharmacokinetics Dynamics & Metabolism, Janssen (Pharmaceutical Companies of Johnson & Johnson) Turnhoutseweg 30 , Beerse , Belgium
| | - James L Stevens
- m Dept of Toxicology , Lilly Research Laboratories, Eli Lilly and Company , Indianapolis , Indiana , USA
| | - Tracy Walker
- n Investigative Safety & Drug Metabolism , GlaxoSmithKline, David Jack Centre for Research and Development , Ware , Herts , Hertfordshire, UK
| | - B Kevin Park
- o Institute of Translational Medicine , University of Liverpool , Liverpool , UK
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Bailey WJ, Glaab W. Derisking drug-induced liver injury from bench to bedside. CURRENT OPINION IN TOXICOLOGY 2017. [DOI: 10.1016/j.cotox.2017.06.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Slopianka M, Herrmann A, Pavkovic M, Ellinger-Ziegelbauer H, Ernst R, Mally A, Keck M, Riefke B. Quantitative targeted bile acid profiling as new markers for DILI in a model of methapyrilene-induced liver injury in rats. Toxicology 2017; 386:1-10. [PMID: 28529062 DOI: 10.1016/j.tox.2017.05.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Revised: 05/08/2017] [Accepted: 05/17/2017] [Indexed: 12/11/2022]
Abstract
Recently, bile acids (BAs) were reported as promising markers for drug-induced liver injury (DILI). BAs have been suggested to correlate with hepatocellular and hepatobiliary damage; however a clear connection of BA patterns with different types of DILI remains to be established. To investigate if BAs can improve the assessment of liver injury, 20 specific BAs were quantitatively profiled via LC-MS/MS in plasma and liver tissue in a model of methapyrilene-induced liver injury in rats. Methapyrilene, a known hepatotoxin was dosed daily over 14-days at doses of 30 and 80mg/kg, followed by a recovery phase of 10days. Conventional preclinical safety endpoints were related to BA perturbations and to hepatic gene expression profiling for a mechanistic interpretation of effects. Histopathological signs of hepatocellular and hepatobiliary damage with significant changes of clinical chemistry markers were accompanied by significantly increased levels of indivdual BAs in plasma and liver tissue. BA perturbations were already evident at the earliest time point after 30mg/kg treatment, and thereby indicating better sensitivity than clinical chemistry parameters. Furthermore, the latter markers suggested recovery of liver injury, whereas BA levels in plasma and liver remained significantly elevated during the recovery phase, in line with persistent histopathological findings of bile duct hyperplasia (BDH) and bile pigment deposition. Gene expression profiling revealed downregulation of genes involved in BA synthesis (AMACR, BAAT, ACOX2) and hepatocellular uptake (NTCP, OATs), and upregulation for efflux transporters (MRP2, MRP4), suggesting an adaptive hepatocellular protection mechanism against cytotoxic bile acid accumulation. In summary, our data suggests that specific BAs with high reliability such as cholic acid (CA) and chenodeoxycholic acid (CDCA) followed by glycocholic acid (GCA), taurocholic acid (TCA) and deoxycholic acid (DCA) can serve as additional biomarkers for hepatocellular/hepatobiliary damage in the liver in rat toxicity studies.
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Affiliation(s)
- Markus Slopianka
- Bayer AG, Investigational Toxicology, Muellerstraße 178, 13353 Berlin, Germany; University Wuerzburg, Department of Toxicology, Versbacher Straße 9, 97078 Wuerzburg, Germany.
| | - Anne Herrmann
- Bayer AG, Investigational Toxicology, Muellerstraße 178, 13353 Berlin, Germany.
| | - Mira Pavkovic
- Bayer AG, Biomarker Research, Aprather Weg 18a, 42096 Wuppertal, Germany.
| | | | - Rainer Ernst
- Bayer AG, Pathology and Clinical Pathology, Muellerstraße 178, Building S116, 13353 Berlin, Germany.
| | - Angela Mally
- University Wuerzburg, Department of Toxicology, Versbacher Straße 9, 97078 Wuerzburg, Germany.
| | - Matthias Keck
- Bayer AG, Investigational Toxicology, Muellerstraße 178, 13353 Berlin, Germany.
| | - Bjoern Riefke
- Bayer AG, Investigational Toxicology, Muellerstraße 178, 13353 Berlin, Germany.
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Loosen SH, Schueller F, Trautwein C, Roy S, Roderburg C. Role of circulating microRNAs in liver diseases. World J Hepatol 2017; 9:586-594. [PMID: 28515844 PMCID: PMC5411953 DOI: 10.4254/wjh.v9.i12.586] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Revised: 03/27/2017] [Accepted: 04/10/2017] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are small RNAs regulate gene expression by inhibiting the turnover of their target mRNAs. In the last years, it became apparent that miRNAs are released into the circulation and circulating miRNAs emerged as a new class of biomarkers for various diseases. In this review we summarize available data on the role of circulating miRNAs in the context of acute and chronic liver diseases including hepatocellular and cholangiocellular carcinoma. Data from animal models are compared to human data and current challenges in the field of miRNAs research are discussed.
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Model Systems for Studying the Role of Canalicular Efflux Transporters in Drug-Induced Cholestatic Liver Disease. J Pharm Sci 2017; 106:2295-2301. [PMID: 28385542 DOI: 10.1016/j.xphs.2017.03.023] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2016] [Revised: 03/11/2017] [Accepted: 03/27/2017] [Indexed: 12/12/2022]
Abstract
Bile formation is a key function of the liver. Disturbance of bile flow may lead to liver disease and is called cholestasis. Cholestasis may be inherited, for example, in progressive familial intrahepatic cholestasis or acquired, for example, by drug-mediated inhibition of bile salt export from hepatocytes into the canaliculi. The key transport system for exporting bile salts into the canaliculi is the bile salt export pump. Inhibition of the bile salt export pump by drugs is a well-established cause of drug-induced cholestasis. Investigation of the role of the multidrug resistance protein 3, essential for biliary phospholipid secretion, is emerging now. This overview summarizes current concepts and methods with an emphasis on in vitro model systems for the investigation of drug-induced cholestasis in the general context of drug-induced liver injury.
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