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Qian J, Feng C, Wu Z, Yang Y, Gao X, Zhu L, Liu Y, Gao Y. Phytochemistry, pharmacology, toxicology and detoxification of Polygonum multiflorum Thunb.: a comprehensive review. Front Pharmacol 2024; 15:1427019. [PMID: 38953108 PMCID: PMC11215120 DOI: 10.3389/fphar.2024.1427019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Accepted: 05/29/2024] [Indexed: 07/03/2024] Open
Abstract
Background Polygonum multiflorum Thunb. (PM), a kind of perennial plant, belongs to the genus Polygonum of the family polygonaceae.The dry root of PM (also called Heshouwu), is a traditional Chinese medicine, which has a series of functions and is widely used in clinic for hair lossing, aging, and insomnia. While, PM also has some toxicity, its clinical drug safety has been concerned. In this paper, the chemical components, toxic mechanisms and detoxification strategies of PM were reviewed in order to provide evidence for its clinical application. Materials and methods We conducted a systematic review of published literature of PM, including English and Chinese databases, such as PubMed, Web of Science, CNKI, and Wanfang. Results PM contains a variety of chemical compounds, including stilbenes, quinones, flavonoids, phospholipids, and has many pharmacological activities such as anti-aging, wound healing, antioxidant, and anti-inflammatory properties. The PE has certain therapeutic effect, and it has certain toxicity like hepatotoxicity, nephrotoxicity, and embryotoxicity at the same time, but.these toxic effects could be effectively reduced by processing and compatibility. Conclusion It is necessary to further explore the pharmacological and toxicological mechanisms of the main active compounds of PE.This article provides scientific basis for the safe clinical application of PM.
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Affiliation(s)
- Jiawen Qian
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Chenhang Feng
- The Third Affiliated Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Ziyang Wu
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Yuanmei Yang
- School of Pharmacy, Fudan University, Shanghai, China
| | - Xiangfu Gao
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Lingyan Zhu
- Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yang Liu
- Shaanxi Academy of Traditional Chinese Medicine, Xi’an, China
| | - Yuancheng Gao
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
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2
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Boudreau MW, Mulligan MP, Shapiro DJ, Fan TM, Hergenrother PJ. Activators of the Anticipatory Unfolded Protein Response with Enhanced Selectivity for Estrogen Receptor Positive Breast Cancer. J Med Chem 2022; 65:3894-3912. [PMID: 35080871 PMCID: PMC9067622 DOI: 10.1021/acs.jmedchem.1c01730] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Approximately 75% of breast cancers are estrogen receptor alpha-positive (ERα+), and targeting ERα directly with ERα antagonists/degraders or indirectly with aromatase inhibitors is a successful therapeutic strategy. However, such treatments are rarely curative and development of resistance is universal. We recently reported ErSO, a compound that induces ERα-dependent cancer cell death through a mechanism distinct from clinically approved ERα drugs, via hyperactivation of the anticipatory unfolded protein response. ErSO has remarkable tumor-eradicative activity in multiple ERα+ tumor models. While ErSO has promise as a new drug, it has effects on ERα-negative (ERα-) cells in certain contexts. Herein, we construct modified versions of ErSO and identify variants with enhanced differential activity between ERα+ and ERα- cells. We report ErSO-DFP, a compound that maintains antitumor efficacy, has enhanced selectivity for ERα+ cancer cells, and is well tolerated in rodents. ErSO-DFP and related compounds represent an intriguing new class for the treatment of ERα+ cancers.
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Affiliation(s)
- Matthew W. Boudreau
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, 61801, United States,Carl R. Woese Institute for Genomic, Biology University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States
| | - Michael P. Mulligan
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States,Carl R. Woese Institute for Genomic Biology University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States
| | - David J. Shapiro
- Cancer Center at Illinois and Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States
| | - Timothy M. Fan
- Carl R. Woese Institute for Genomic Biology University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States,Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States,Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois 61802, United States
| | - Paul J. Hergenrother
- Department of Chemistry and Cancer, Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States,Carl R. Woese Institute for Genomic Biology University of Illinois at, Urbana-Champaign, Urbana, Illinois 61801, United States
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Girish C, Sanjay S. Role of immune dysfunction in drug induced liver injury. World J Hepatol 2021; 13:1677-1687. [PMID: 34904037 PMCID: PMC8637670 DOI: 10.4254/wjh.v13.i11.1677] [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: 04/03/2021] [Revised: 07/15/2021] [Accepted: 09/17/2021] [Indexed: 02/06/2023] Open
Abstract
Drug-induced liver injury (DILI) is one of the leading causes of liver failure and withdrawal of drugs from the market. A poor understanding of the precipitating event aetiology and mechanisms of disease progression has rendered the prediction and subsequent treatment intractable. Recent literature suggests that some drugs can alter the liver’s repair systems resulting in injury. The pathophysiology of DILI is complex, and immune dysfunction plays an important role in determining the course and severity of the disease. Immune dysfunction is influenced by the host response to drug toxicity. A deeper understanding of these processes may be beneficial in the management of DILI and aid in drug development. This review provides a structured framework presenting DILI in three progressive stages that summarize the interplay between drugs and the host defence networks.
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Affiliation(s)
- Chandrashekaran Girish
- Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Sukumaran Sanjay
- Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
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4
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Sinha A, Neema S, Manrai M, Vasudevan B, Radhakrishnan S. Drug-Induced Liver Injury. INDIAN JOURNAL OF DRUGS IN DERMATOLOGY 2021; 7:106-112. [DOI: 10.4103/ijdd.ijdd_53_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Dermatological practice involves the use of systemic drugs; some of them carrying boxed warnings of hepatotoxicity while others causing inadvertent or idiosyncratic liver damage. Drug-induced liver injury (DILI) is a common problem faced by dermatologists and refers to liver damage caused by medications, herbs, or other xenobiotics which can sometimes be fatal. Diagnosis of DILI remains challenging due to nonspecific clinical presentations compounded by a lack of knowledge in this area. With careful patient selection and systematic monitoring, liver injury should be rare in the dermatological setup. This review article is written with the aim of increasing awareness of DILI among dermatologists and thereby preventing liver injuries from common drugs.
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5
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Teschke R, Uetrecht J. Mechanism of idiosyncratic drug induced liver injury (DILI): unresolved basic issues. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:730. [PMID: 33987428 PMCID: PMC8106057 DOI: 10.21037/atm-2020-ubih-05] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Clinical features of idiosyncratic drug induced liver injury (DILI) are well described in cases that have been assessed for causality using the Roussel Uclaf Causality Assessment Method (RUCAM), but our understanding of the mechanistic steps leading to injury is fragmentary. The difficulties describing mechanistic events can be traced back to the lack of an animal model of experimental idiosyncratic DILI that can mimic the genetic requirements of human idiosyncratic DILI. However, immune tolerance plays a dominant role in the immune response of the liver, and impairment of immune tolerance with immune checkpoint inhibitors increases DILI in both humans and animals. This may provide one method to study the individual steps involved. In general. the human DILI liver is a secret keeper providing little insight into what occurs in the diseased organ. Sufficient evidence exists that most idiosyncratic cases are mediated by the adaptive immune system, which depends on stimulation of the innate immune system, but the triggering factors are unknown. It is attractive to hypothesize that the gut microbiome plays a role; however, it is very difficult to study. Similarly, exosomes are likely to play an important role in communication between hepatic cells and the immune system, but there is a lack of data on blood exosomes in affected patients. Reactive metabolites are likely to play an important role. This is supported by the current analysis, which revealed an association between metabolism by cytochrome P450 and drugs most commonly involved in causing idiosyncratic DILI with causality verified by RUCAM. Circumstantial evidence suggests that reactive oxygen species (ROS) generated by cytochrome P450 could be responsible for the initial steps of injury, but details are unknown. In conclusion, most of the mechanistic steps leading to idiosyncratic DILI remain unclear.
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Affiliation(s)
- Rolf Teschke
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Hanau, Academic Teaching Hospital of the Medical Faculty of the Goethe University Frankfurt/ Main, Frankfurt/Main, Germany
| | - Jack Uetrecht
- Department of Pharmaceutical Sciences, University of Toronto, ON, Canada
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6
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Teschke R, Danan G. Idiosyncratic Drug Induced Liver Injury, Cytochrome P450, Metabolic Risk Factors and Lipophilicity: Highlights and Controversies. Int J Mol Sci 2021; 22:3441. [PMID: 33810530 PMCID: PMC8037096 DOI: 10.3390/ijms22073441] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 03/19/2021] [Accepted: 03/22/2021] [Indexed: 12/16/2022] Open
Abstract
Progress in understanding the mechanisms of the idiosyncratic drug induced liver injury (iDILI) was highlighted in a scientometric investigation on the knowledge mapping of iDILI throughout the world, but uncertainty remained on metabolic risk factors of iDILI, the focus of the present review article. For the first time, a quantitative analysis of 3312 cases of iDILI assessed for causality with RUCAM (Roussel Uclaf Causality Assessment Method) showed that most drugs (61.1%) were metabolized by cytochrome P450 (CYP) isoforms: 49.6% by CYP 3A4/5, 24.6% by CYP 2C9, 13.2% by CYP 2E1, 7.3% by CYP 2C19, 3.5% by CYP 1A2 and 1.8% by CYP 2D6. Other studies showed high OR (odds ratio) for drugs metabolized by unspecified CYPs but the iDILI cases were not assessed for causality with RUCAM, a major shortcoming. In addition to critical comments on methodological flaws, several risk factors of iDILI were identified such as high but yet recommended daily drug doses, actual daily drug doses taken by the patients, hepatic drug metabolism and drug lipophilicity. These risk factors are subject to controversies by many experts seen critically also by others who outlined that none of these medication characteristics is able to predict iDILI with high confidence, leading to the statement of an outstanding caveat. It was also argued that all previous studies lacked comprehensive data because the number of examined drugs was relatively small as compared to the number of approved new molecular entities or currently used oral prescription drugs. In conclusion, trends are evident that some metabolic parameters are likely risk factors of iDILI but strong evidence can only be achieved when methodological issues will be successfully met.
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Affiliation(s)
- Rolf Teschke
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, D-63450 Hanau, Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/Main, 60323 Frankfurt/Main, Germany
| | - Gaby Danan
- Pharmacovigilance Consultancy, F-75020 Paris, France;
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7
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Hughes TB, Flynn N, Dang NL, Swamidass SJ. Modeling the Bioactivation and Subsequent Reactivity of Drugs. Chem Res Toxicol 2021; 34:584-600. [PMID: 33496184 DOI: 10.1021/acs.chemrestox.0c00417] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Electrophilically reactive drug metabolites are implicated in many adverse drug reactions. In this mechanism-termed bioactivation-metabolic enzymes convert drugs into reactive metabolites that often conjugate to nucleophilic sites within biological macromolecules like proteins. Toxic metabolite-product adducts induce severe immune responses that can cause sometimes fatal disorders, most commonly in the form of liver injury, blood dyscrasia, or the dermatologic conditions toxic epidermal necrolysis and Stevens-Johnson syndrome. This study models four of the most common metabolic transformations that result in bioactivation: quinone formation, epoxidation, thiophene sulfur-oxidation, and nitroaromatic reduction, by synthesizing models of metabolism and reactivity. First, the metabolism models predict the formation probabilities of all possible metabolites among the pathways studied. Second, the exact structures of these metabolites are enumerated. Third, using these structures, the reactivity model predicts the reactivity of each metabolite. Finally, a feedfoward neural network converts the metabolism and reactivity predictions to a bioactivation prediction for each possible metabolite. These bioactivation predictions represent the joint probability that a metabolite forms and that this metabolite subsequently conjugates to protein or glutathione. Among molecules bioactivated by these pathways, we predicted the correct pathway with an AUC accuracy of 89.98%. Furthermore, the model predicts whether molecules will be bioactivated, distinguishing bioactivated and nonbioactivated molecules with 81.06% AUC. We applied this algorithm to withdrawn drugs. The known bioactivation pathways of alclofenac and benzbromarone were identified by the algorithm, and high probability bioactivation pathways not yet confirmed were identified for safrazine, zimelidine, and astemizole. This bioactivation model-the first of its kind that jointly considers both metabolism and reactivity-enables drug candidates to be quickly evaluated for a toxicity risk that often evades detection during preclinical trials. The XenoSite bioactivation model is available at http://swami.wustl.edu/xenosite/p/bioactivation.
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Affiliation(s)
- Tyler B Hughes
- Department of Pathology and Immunology, Washington University School of Medicine, Campus Box 8118, 660 South Euclid Avenue, St. Louis, Missouri 63110, United States
| | - Noah Flynn
- Department of Pathology and Immunology, Washington University School of Medicine, Campus Box 8118, 660 South Euclid Avenue, St. Louis, Missouri 63110, United States
| | - Na Le Dang
- Department of Pathology and Immunology, Washington University School of Medicine, Campus Box 8118, 660 South Euclid Avenue, St. Louis, Missouri 63110, United States
| | - S Joshua Swamidass
- Department of Pathology and Immunology, Washington University School of Medicine, Campus Box 8118, 660 South Euclid Avenue, St. Louis, Missouri 63110, United States
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8
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Hughes TB, Dang NL, Kumar A, Flynn NR, Swamidass SJ. Metabolic Forest: Predicting the Diverse Structures of Drug Metabolites. J Chem Inf Model 2020; 60:4702-4716. [PMID: 32881497 PMCID: PMC8716321 DOI: 10.1021/acs.jcim.0c00360] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Adverse drug metabolism often severely impacts patient morbidity and mortality. Unfortunately, drug metabolism experimental assays are costly, inefficient, and slow. Instead, computational modeling could rapidly flag potentially toxic molecules across thousands of candidates in the early stages of drug development. Most metabolism models focus on predicting sites of metabolism (SOMs): the specific substrate atoms targeted by metabolic enzymes. However, SOMs are merely a proxy for metabolic structures: knowledge of an SOM does not explicitly provide the actual metabolite structure. Without an explicit metabolite structure, computational systems cannot evaluate the new molecule's properties. For example, the metabolite's reactivity cannot be automatically predicted, a crucial limitation because reactive drug metabolites are a key driver of adverse drug reactions (ADRs). Additionally, further metabolic events cannot be forecast, even though the metabolic path of the majority of substrates includes two or more sequential steps. To overcome the myopia of the SOM paradigm, this study constructs a well-defined system-termed the metabolic forest-for generating exact metabolite structures. We validate the metabolic forest with the substrate and product structures from a large, chemically diverse, literature-derived dataset of 20 736 records. The metabolic forest finds a pathway linking each substrate and product for 79.42% of these records. By performing a breadth-first search of depth two or three, we improve performance to 88.43 and 88.77%, respectively. The metabolic forest includes a specialized algorithm for producing accurate quinone structures, the most common type of reactive metabolite. To our knowledge, this quinone structure algorithm is the first of its kind, as the diverse mechanisms of quinone formation are difficult to systematically reproduce. We validate the metabolic forest on a previously published dataset of 576 quinone reactions, predicting their structures with a depth three performance of 91.84%. The metabolic forest accurately enumerates metabolite structures, enabling promising new directions such as joint metabolism and reactivity modeling.
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Affiliation(s)
- Tyler B Hughes
- Department of Pathology and Immunology, Washington University School of Medicine, Campus Box 8118, 660 South Euclid Avenue, St. Louis, Missouri 63110, United States
| | - Na Le Dang
- Department of Pathology and Immunology, Washington University School of Medicine, Campus Box 8118, 660 South Euclid Avenue, St. Louis, Missouri 63110, United States
| | - Ayush Kumar
- Department of Pathology and Immunology, Washington University School of Medicine, Campus Box 8118, 660 South Euclid Avenue, St. Louis, Missouri 63110, United States
| | - Noah R Flynn
- Department of Pathology and Immunology, Washington University School of Medicine, Campus Box 8118, 660 South Euclid Avenue, St. Louis, Missouri 63110, United States
| | - S Joshua Swamidass
- Department of Pathology and Immunology, Washington University School of Medicine, Campus Box 8118, 660 South Euclid Avenue, St. Louis, Missouri 63110, United States
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9
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Busche M, Tomilova O, Schütte J, Werner S, Beer M, Groll N, Hagmeyer B, Pawlak M, Jones PD, Schmees C, Becker H, Schnabel J, Gall K, Hemmler R, Matz-Soja M, Damm G, Beuck S, Klaassen T, Moer J, Ullrich A, Runge D, Schenke-Layland K, Gebhardt R, Stelzle M. HepaChip-MP - a twenty-four chamber microplate for a continuously perfused liver coculture model. LAB ON A CHIP 2020; 20:2911-2926. [PMID: 32662810 DOI: 10.1039/d0lc00357c] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
HepaChip microplate (HepaChip-MP) is a microfluidic platform comprised of 24 independent culture chambers with continuous, unidirectional perfusion. In the HepaChip-MP, an automated dielectrophoresis process selectively assembles viable cells into elongated micro tissues. Freshly isolated primary human hepatocytes (PHH) and primary human liver endothelial cells (HuLEC) were successfully assembled as cocultures aiming to mimic the liver sinusoid. Minimal quantities of primary human cells are required to establish micro tissues in the HepaChip-MP. Metabolic function including induction of CYP enzymes in PHH was successfully measured demonstrating a high degree of metabolic activity of cells in HepaChip-MP cultures and sufficient sensitivity of LC-MS analysis even for the relatively small number of cells per chamber. Further, parallelization realized in HepaChip-MP enabled the acquisition of dose-response toxicity data of diclofenac with a single device. Several unique technical features should enable a widespread application of this in vitro model. We have demonstrated fully automated preparation of cell cultures in HepaChip-MP using a pipetting robot. The tubeless unidirectional perfusion system based on gravity-driven flow can be operated within a standard incubator system. Overall, the system readily integrates in workflows common in cell culture labs. Further research will be directed towards optimization of media composition to further extend culture lifetime and study oxygen gradients and their effect on zonation within the sinusoid-like microorgans. In summary, we have established a novel parallelized and scalable microfluidic in vitro liver model showing hepatocyte function and anticipate future in-depth studies of liver biology and applications in pre-clinical drug development.
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Affiliation(s)
- Marius Busche
- NMI Natural and Medical Sciences Institute, University of Tübingen, Reutlingen, Germany.
| | - Olena Tomilova
- NMI Natural and Medical Sciences Institute, University of Tübingen, Reutlingen, Germany.
| | - Julia Schütte
- NMI Natural and Medical Sciences Institute, University of Tübingen, Reutlingen, Germany.
| | - Simon Werner
- NMI Natural and Medical Sciences Institute, University of Tübingen, Reutlingen, Germany.
| | - Meike Beer
- NMI Natural and Medical Sciences Institute, University of Tübingen, Reutlingen, Germany.
| | - Nicola Groll
- NMI Natural and Medical Sciences Institute, University of Tübingen, Reutlingen, Germany.
| | - Britta Hagmeyer
- NMI Natural and Medical Sciences Institute, University of Tübingen, Reutlingen, Germany.
| | - Michael Pawlak
- NMI Natural and Medical Sciences Institute, University of Tübingen, Reutlingen, Germany.
| | - Peter D Jones
- NMI Natural and Medical Sciences Institute, University of Tübingen, Reutlingen, Germany.
| | - Christian Schmees
- NMI Natural and Medical Sciences Institute, University of Tübingen, Reutlingen, Germany.
| | | | | | | | | | - Madlen Matz-Soja
- Section of Hepatology, Clinic and Polyclinic for Gastroenterology, Hepatology, Infectiology, Pneumology, University Clinic Leipzig, Leipzig, Germany and Rudolf-Schönheimer-Institute of Biochemistry, Leipzig University, Leipzig, Germany
| | - Georg Damm
- Department of Hepatobiliary Surgery and Visceral Transplantation, University Hospital, Leipzig University, Leipzig, Germany
| | - Simon Beuck
- A & M Labor fuer Analytik und Metabolismusforschung Service GmbH, Bergheim, Germany
| | - Tobias Klaassen
- A & M Labor fuer Analytik und Metabolismusforschung Service GmbH, Bergheim, Germany
| | - Jana Moer
- PRIMACYT Cell Culture Technology GmbH, Schwerin, Germany
| | - Anett Ullrich
- PRIMACYT Cell Culture Technology GmbH, Schwerin, Germany
| | - Dieter Runge
- PRIMACYT Cell Culture Technology GmbH, Schwerin, Germany
| | - Katja Schenke-Layland
- NMI Natural and Medical Sciences Institute, University of Tübingen, Reutlingen, Germany. and Department of Women's Health, Research Institute for Women's Health, Eberhard Karls University Tübingen, Tübingen, Germany and Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", Eberhard Karls University Tübingen, Germany and Department of Medicine/Cardiology, Cardiovascular Research Laboratories (CVRL), University of California (UCLA), Los Angeles, CA, USA
| | - Rolf Gebhardt
- Section of Hepatology, Clinic and Polyclinic for Gastroenterology, Hepatology, Infectiology, Pneumology, University Clinic Leipzig, Leipzig, Germany and Rudolf-Schönheimer-Institute of Biochemistry, Leipzig University, Leipzig, Germany and InViSys-Tübingen GbR, Leipzig, Germany
| | - Martin Stelzle
- NMI Natural and Medical Sciences Institute, University of Tübingen, Reutlingen, Germany.
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10
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Andrade RJ, Chalasani N, Björnsson ES, Suzuki A, Kullak-Ublick GA, Watkins PB, Devarbhavi H, Merz M, Lucena MI, Kaplowitz N, Aithal GP. Drug-induced liver injury. Nat Rev Dis Primers 2019; 5:58. [PMID: 31439850 DOI: 10.1038/s41572-019-0105-0] [Citation(s) in RCA: 439] [Impact Index Per Article: 73.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/04/2019] [Indexed: 02/06/2023]
Abstract
Drug-induced liver injury (DILI) is an adverse reaction to drugs or other xenobiotics that occurs either as a predictable event when an individual is exposed to toxic doses of some compounds or as an unpredictable event with many drugs in common use. Drugs can be harmful to the liver in susceptible individuals owing to genetic and environmental risk factors. These risk factors modify hepatic metabolism and excretion of the DILI-causative agent leading to cellular stress, cell death, activation of an adaptive immune response and a failure to adapt, with progression to overt liver injury. Idiosyncratic DILI is a relative rare hepatic disorder but can be severe and, in some cases, fatal, presenting with a variety of phenotypes, which mimic other hepatic diseases. The diagnosis of DILI relies on the exclusion of other aetiologies of liver disease as specific biomarkers are still lacking. Clinical scales such as CIOMS/RUCAM can support the diagnostic process but need refinement. A number of clinical variables, validated in prospective cohorts, can be used to predict a more severe DILI outcome. Although no pharmacological therapy has been adequately tested in randomized clinical trials, corticosteroids can be useful, particularly in the emergent form of DILI related to immune-checkpoint inhibitors in patients with cancer.
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Affiliation(s)
- Raul J Andrade
- Unidad de Gestión Clínica de Enfermedades Digestivas, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Malaga, Spain. .,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
| | - Naga Chalasani
- Division of Gastroenterology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Einar S Björnsson
- Department of Gastroenterology, Landspitali University Hospital Reykjavik, University of Iceland, Reykjavík, Iceland.,Faculty of Medicine, University of Iceland, Reykjavík, Iceland
| | - Ayako Suzuki
- Gastroenterology, Duke University, Durham, NC, USA.,Gastroenterology, Durham VA Medical Centre, Durham, NC, USA
| | - Gerd A Kullak-Ublick
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.,Mechanistic Safety, CMO & Patient Safety, Global Drug Development, Novartis Pharma, Basel, Switzerland
| | - Paul B Watkins
- UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.,University of North Carolina Institute for Drug Safety Sciences, Research Triangle Park, Chapel Hill, NC, USA
| | - Harshad Devarbhavi
- Department of Gastroenterology and Hepatology, St. John's Medical College Hospital, Bangalore, India
| | - Michael Merz
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.,Patient Safety, AstraZeneca, Gaithersburg, MD, USA
| | - M Isabel Lucena
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain. .,Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, UICEC SCReN, Universidad de Málaga, Málaga, Spain.
| | - Neil Kaplowitz
- Division of Gastroenterology and Liver Diseases, Department of Medicine, Keck School of Medicine, Los Angeles, CA, USA
| | - Guruprasad P Aithal
- National Institute for Health Research (NIHR) Nottingham Digestive Diseases Biomedical Research Centre, Nottingham University Hospital NHS Trust and University of Nottingham, Nottingham, UK
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11
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Metabolic Comorbidities and Risk of Development and Severity of Drug-Induced Liver Injury. BIOMED RESEARCH INTERNATIONAL 2019; 2019:8764093. [PMID: 31531370 PMCID: PMC6720367 DOI: 10.1155/2019/8764093] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 07/09/2019] [Accepted: 07/25/2019] [Indexed: 12/15/2022]
Abstract
The incidence and rates of diagnosis of drug-induced liver injury (DILI) have been increasing in recent years as findings from basic research and the examination of clinical databases reveal information about the clinical course, etiology, and prognosis of this complex disease. The prevalence of metabolic comorbidities (e.g., diabetes mellitus, fatty liver, obesity, and metabolic syndrome (MetS)) has been increasing during the same period. The results of preclinical and clinical research studies indicate that characteristics of metabolic comorbidities are also factors that affect DILI phenotype and progression. The objective of this review is to present the evidence for DILI and hepatotoxicity mechanisms, incidence, and outcomes in patients with MetS and nonalcoholic fatty liver disease. Moreover, we also summarize the relationships between drugs used to treat metabolic comorbidities and DILI.
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Andrade RJ, Aithal GP, Björnsson ES, Kaplowitz N, Kullak-Ublick GA, Larrey D, Karlsen TH. EASL Clinical Practice Guidelines: Drug-induced liver injury. J Hepatol 2019; 70:1222-1261. [PMID: 30926241 DOI: 10.1016/j.jhep.2019.02.014] [Citation(s) in RCA: 645] [Impact Index Per Article: 107.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 02/14/2019] [Indexed: 02/07/2023]
Abstract
Idiosyncratic (unpredictable) drug-induced liver injury is one of the most challenging liver disorders faced by hepatologists, because of the myriad of drugs used in clinical practice, available herbs and dietary supplements with hepatotoxic potential, the ability of the condition to present with a variety of clinical and pathological phenotypes and the current absence of specific biomarkers. This makes the diagnosis of drug-induced liver injury an uncertain process, requiring a high degree of awareness of the condition and the careful exclusion of alternative aetiologies of liver disease. Idiosyncratic hepatotoxicity can be severe, leading to a particularly serious variety of acute liver failure for which no effective therapy has yet been developed. These Clinical Practice Guidelines summarize the available evidence on risk factors, diagnosis, management and risk minimization strategies for drug-induced liver jury.
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Li X, Wang L, Li D, Niu J, Gao P. Dyslipidemia is a Risk Factor for the Incidence and Severity of Drug-Induced Liver Injury (DILI): A Retrospective Population-Based Study in China. Med Sci Monit 2019; 25:3344-3353. [PMID: 31059494 PMCID: PMC6515978 DOI: 10.12659/msm.916687] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Background A Chinese population-based study aimed to investigate the risk factors for the incidence and severity of drug-induced liver injury (DILI) from Chinese herbal medicines and conventional Western medicines. Material/Methods Liver biopsy and routine laboratory testing, including serum lipid measurements, was performed on 465 patients, including 168 patients with DILI and 297 patients without DILI. Histological grading of DILI used the METAVIR scoring system and the severity of DILI was graded as levels 0–5. Multivariate and univariate regression analysis were used to compare the two study groups, using a risk-adjusted odds ratio (AOR). Results There was no significant association between age, alcohol status, cardiovascular disease (CVD), hypertension, or type 2 diabetes mellitus and development of DILI. However, when compared with controls, patients with dyslipidemia (AOR, 2.173; 95% CI, 1.388–3.401; P=0.001) had an increased incidence of DILI, and men had a reduced incidence of DILI when compared with women (AOR, 0.276; 95% CI, 0.169–0.450; P<0.001). Risk factors for severe DILI (≥level 3) included drinking alcohol (AOR, 6.506; 95% CI, 2.184–19.384; P=0.001), and dyslipidemia (AOR, 3.095; 95% CI, 1.345–7.123; P=0.008). Patients with an increased duration of drug treatment of >1 year had a reduced risk of developing severe DILI compared with patients with a medication duration of ≤1 month (AOR, 0.259; 95% CI, 0.084–0.802). Conclusions Increased risk of the incidence of DILI was significantly associated with female gender and dyslipidemia, and the risk of developing severe DILI was associated with drinking alcohol and dyslipidemia.
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Affiliation(s)
- Xu Li
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin, China (mainland)
| | - Le Wang
- Department of Ultrasound, The First Hospital of Jilin University, Jilin University, Changchun, Jilin, China (mainland)
| | - Dezhao Li
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin, China (mainland)
| | - Junqi Niu
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin, China (mainland)
| | - Pujun Gao
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin, China (mainland)
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Chen M, Zhu J, Ashby K, Wu L, Liu Z, Gong P, Zhang C, Borlak J, Hong H, Tong W. Predicting the Risks of Drug-Induced Liver Injury in Humans Utilizing Computational Modeling. CHALLENGES AND ADVANCES IN COMPUTATIONAL CHEMISTRY AND PHYSICS 2019:259-278. [DOI: 10.1007/978-3-030-16443-0_13] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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Chan R, Benet LZ. Evaluation of the Relevance of DILI Predictive Hypotheses in Early Drug Development: Review of In Vitro Methodologies vs BDDCS Classification. Toxicol Res (Camb) 2018; 7:358-370. [PMID: 29785262 DOI: 10.1039/c8tx00016f] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Drug-induced liver injury (DILI) is a major safety concern; it occurs frequently; it is idiosyncratic; it cannot be adequately predicted; and a multitude of underlying mechanisms has been postulated. A number of experimental approaches to predict human DILI have been proposed utilizing in vitro screening such as inhibition of mitochondrial function, hepatobiliary transporter inhibition, reactive metabolite formation with and without covalent binding, and cellular health, but they have achieved only minimal success. Several studies have shown total administered dose alone or in combination with drug lipophilicity to be correlated with a higher risk of DILI. However, it would be best to have a predictive DILI methodology early in drug development, long before the clinical dose is known. Here we discuss the extent to which Biopharmaceutics Drug Disposition Classification System (BDDCS) defining characteristics, independent of knowing actual drug pharmacokinetics/pharmacodynamics and dose, can be used to evaluate prior published predictive proposals. Our results show that BDDCS Class 2 drugs exhibit the highest DILI severity, and that all of the short-lived published methodologies evaluated here, except when daily dose is known, do not yield markedly better predictions than BDDCS. The assertion that extensively metabolized compounds are at higher risk of developing DILI is confirmed, but can be enhanced by differentiating BDDCS Class 2 from Class 1 drugs. CONCLUSION Our published analyses suggest that comparison of proposed DILI prediction methodologies with BDDCS classification is a useful tool to evaluate the potential reliability of newly proposed algorithms, although BDDCS classification itself is not sufficiently predictive. Almost all of the predictive DILI metrics do no better than just avoiding BDDCS Class 2 drugs, although some early data with microliver platforms enabling long-enduring metabolic competency show promising results.
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Affiliation(s)
- Rosa Chan
- Department of Bioengineering and Therapeutic Sciences Schools of Pharmacy and Medicine University of California, San Francisco
| | - Leslie Z Benet
- Department of Bioengineering and Therapeutic Sciences Schools of Pharmacy and Medicine University of California, San Francisco
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Johnson TW, Gallego RA, Edwards MP. Lipophilic Efficiency as an Important Metric in Drug Design. J Med Chem 2018; 61:6401-6420. [DOI: 10.1021/acs.jmedchem.8b00077] [Citation(s) in RCA: 136] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Ted W. Johnson
- Oncology Medicinal Chemistry, Pfizer Inc., 10770 Science Center Drive, La Jolla, California 92121, United States
| | - Rebecca A. Gallego
- Oncology Medicinal Chemistry, Pfizer Inc., 10770 Science Center Drive, La Jolla, California 92121, United States
| | - Martin P. Edwards
- Oncology Medicinal Chemistry, Pfizer Inc., 10770 Science Center Drive, La Jolla, California 92121, United States
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McEuen K, Borlak J, Tong W, Chen M. Associations of Drug Lipophilicity and Extent of Metabolism with Drug-Induced Liver Injury. Int J Mol Sci 2017; 18:E1335. [PMID: 28640208 PMCID: PMC5535828 DOI: 10.3390/ijms18071335] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Revised: 06/13/2017] [Accepted: 06/15/2017] [Indexed: 12/11/2022] Open
Abstract
Drug-induced liver injury (DILI), although rare, is a frequent cause of adverse drug reactions resulting in warnings and withdrawals of numerous medications. Despite the research community's best efforts, current testing strategies aimed at identifying hepatotoxic drugs prior to human trials are not sufficiently powered to predict the complex mechanisms leading to DILI. In our previous studies, we demonstrated lipophilicity and dose to be associated with increased DILI risk and, and in our latest work, we factored reactive metabolites into the algorithm to predict DILI. Given the inconsistency in determining the potential for drugs to cause DILI, the present study comprehensively assesses the relationship between DILI risk and lipophilicity and the extent of metabolism using a large published dataset of 1036 Food and Drug Administration (FDA)-approved drugs by considering five independent DILI annotations. We found that lipophilicity and the extent of metabolism alone were associated with increased risk for DILI. Moreover, when analyzed in combination with high daily dose (≥100 mg), lipophilicity was statistically significantly associated with the risk of DILI across all datasets (p < 0.05). Similarly, the combination of extensive hepatic metabolism (≥50%) and high daily dose (≥100 mg) was also strongly associated with an increased risk of DILI among all datasets analyzed (p < 0.05). Our results suggest that both lipophilicity and the extent of hepatic metabolism can be considered important risk factors for DILI in humans, and that this relationship to DILI risk is much stronger when considered in combination with dose. The proposed paradigm allows the convergence of different published annotations to a more uniform assessment.
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Affiliation(s)
- Kristin McEuen
- Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA.
- Department of Information Science, University of Arkansas at Little Rock, Little Rock, AR 72204, USA.
| | - Jürgen Borlak
- Center of Pharmacology and Toxicology, Hannover Medical School, Hannover 30625, Germany.
| | - Weida Tong
- Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA.
| | - Minjun Chen
- Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA.
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Iorga A, Dara L, Kaplowitz N. Drug-Induced Liver Injury: Cascade of Events Leading to Cell Death, Apoptosis or Necrosis. Int J Mol Sci 2017; 18:ijms18051018. [PMID: 28486401 PMCID: PMC5454931 DOI: 10.3390/ijms18051018] [Citation(s) in RCA: 199] [Impact Index Per Article: 24.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Revised: 05/05/2017] [Accepted: 05/07/2017] [Indexed: 12/11/2022] Open
Abstract
Drug-induced liver injury (DILI) can broadly be divided into predictable and dose dependent such as acetaminophen (APAP) and unpredictable or idiosyncratic DILI (IDILI). Liver injury from drug hepatotoxicity (whether idiosyncratic or predictable) results in hepatocyte cell death and inflammation. The cascade of events leading to DILI and the cell death subroutine (apoptosis or necrosis) of the cell depend largely on the culprit drug. Direct toxins to hepatocytes likely induce oxidative organelle stress (such as endoplasmic reticulum (ER) and mitochondrial stress) leading to necrosis or apoptosis, while cell death in idiosyncratic DILI (IDILI) is usually the result of engagement of the innate and adaptive immune system (likely apoptotic), involving death receptors (DR). Here, we review the hepatocyte cell death pathways both in direct hepatotoxicity such as in APAP DILI as well as in IDILI. We examine the known signaling pathways in APAP toxicity, a model of necrotic liver cell death. We also explore what is known about the genetic basis of IDILI and the molecular pathways leading to immune activation and how these events can trigger hepatotoxicity and cell death.
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Affiliation(s)
- Andrea Iorga
- Research Center for Liver Disease, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
| | - Lily Dara
- Research Center for Liver Disease, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
| | - Neil Kaplowitz
- Research Center for Liver Disease, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
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Mishra P, Chen M. Direct-Acting Antivirals for Chronic Hepatitis C: Can Drug Properties Signal Potential for Liver Injury? Gastroenterology 2017; 152:1270-1274. [PMID: 28327365 DOI: 10.1053/j.gastro.2017.03.012] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Affiliation(s)
- Poonam Mishra
- US Food and Drug Administration, Silver Spring, Maryland
| | - Minjun Chen
- US Food and Drug Administration, Jefferson, Arkansas.
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Funk C, Roth A. Current limitations and future opportunities for prediction of DILI from in vitro. Arch Toxicol 2016; 91:131-142. [DOI: 10.1007/s00204-016-1874-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 10/10/2016] [Indexed: 01/07/2023]
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Abstract
Drugs can induce liver injury when taken as an over-dose, or even at therapeutic doses in susceptible individuals. Although severe drug-induced liver injury (DILI) is a relatively uncommon clinical event, it is a potentially life threatening adverse drug reaction and is the most common indication for the drug withdrawal. Areas covered: However, the diagnosis of DILI remains a significant challenge, because the establishment of causality is very difficult, and the histopathologic findings of DILI may be indistinguishable from those of other hepatic disorders, such as viral and alcoholic hepatitis. In this review, we provide an overview of recent advances in identification of serologic markers of diagnosis and prognosis, etiologic factors for susceptibility and diagnostic evaluation of DILI, with a focus on its pathogenic mechanisms and the role of liver biopsy. Expert commentary: Further studies of divergent research platforms, using a systems biology approach such as genomics and transcriptomics, may provide a deeper understanding of human drug metabolism and the causes, risk factors, and pathogenesis of DILI.
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Affiliation(s)
- Sun-Jae Lee
- a Department of Pathology, School of Medicine , Catholic University of Daegu , Daegu , Republic of Korea
| | - Youn Ju Lee
- b Department of Pharmacology, School of Medicine , Catholic University of Daegu , Daegu , Republic of Korea
| | - Kwan-Kyu Park
- a Department of Pathology, School of Medicine , Catholic University of Daegu , Daegu , Republic of Korea
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Chen M, Borlak J, Tong W. A Model to predict severity of drug-induced liver injury in humans. Hepatology 2016; 64:931-40. [PMID: 27302180 DOI: 10.1002/hep.28678] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Revised: 04/27/2016] [Accepted: 05/14/2016] [Indexed: 12/11/2022]
Abstract
UNLABELLED Drug-induced liver injury (DILI) is a major public health concern, and improving its prediction remains an unmet challenge. Recently, we reported the Rule-of-2 (RO2) and found lipophilicity (logP ≥3) and daily dose ≥100 mg of oral medications to be associated with significant risk for DILI; however, the RO2 failed to estimate grades of DILI severity. In an effort to develop a quantitative metrics, we analyzed the association of daily dose, logP, and formation of reactive metabolites (RM) in a large set of Food and Drug Administration-approved oral medications and found factoring RM into the RO2 to highly improve DILI prediction. Based on these parameters and by considering n = 354 drugs, an algorithm to assign a DILI score was developed. In univariate and multivariate logistic regression analyses the algorithm (i.e., DILI score model) defined the relative contribution of daily dose, logP, and RM and permitted a quantitative assessment of risk of clinical DILI. Furthermore, a clear relationship between calculated DILI scores and DILI risk was obtained when applied to three independent studies. The DILI score model was also functional with drug pairs defined by similar chemical structure and mode of action but divergent toxicities. Specifically, for drug pairs where the RO2 failed, the DILI score correctly identified toxic drugs. Finally, the model was applied to n = 159 clinical cases collected from the National Institutes of Health's LiverTox database to demonstrate that the DILI score correlated with the severity of clinical outcome. CONCLUSIONS Based on daily dose, lipophilicity, and RM, a DILI score algorithm was developed that provides a scale of assessing the severity of DILI risk in humans associated with oral medications. (Hepatology 2016;64:931-940).
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Affiliation(s)
- Minjun Chen
- Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR
| | - Jürgen Borlak
- Center of Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany
| | - Weida Tong
- Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR
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Dara L, Liu ZX, Kaplowitz N. Mechanisms of adaptation and progression in idiosyncratic drug induced liver injury, clinical implications. Liver Int 2016; 36:158-65. [PMID: 26484420 PMCID: PMC4718752 DOI: 10.1111/liv.12988] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Accepted: 10/13/2015] [Indexed: 12/13/2022]
Abstract
In the past decade our understanding of idiosyncratic drug induced liver injury (IDILI) and the contribution of genetic susceptibility and the adaptive immune system to the pathogenesis of this disease process has grown tremendously. One of the characteristics of IDILI is that it occurs rarely and only in a subset of individuals with a presumed susceptibility to the drug. Despite a clear association between single nucleotide polymorphisms in human leukocyte antigen (HLA) genes and certain drugs that cause IDILI, not all individuals with susceptible HLA genotypes develop clinically significant liver injury when exposed to drugs. The adaptation hypothesis has been put forth as an explanation for why only a small percentage of susceptible individuals develop overt IDILI and severe injury, while the majority with susceptible genotypes develop only mild abnormalities that resolve spontaneously upon continuation of the drug. This spontaneous resolution is referred to as clinical adaptation. Failure to adapt or defective adaptation leads to clinically significant liver injury. In this review we explore the immuno-tolerant microenvironment of the liver and the mechanisms of clinical adaptation in IDILI with a focus on the role of immune-tolerance and cellular adaptive responses.
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Affiliation(s)
- Lily Dara
- Research Center for Liver Disease, Keck School of Medicine, University of Southern California, Los Angeles CA
| | - Zhang-Xu Liu
- Research Center for Liver Disease, Keck School of Medicine, University of Southern California, Los Angeles CA
| | - Neil Kaplowitz
- Research Center for Liver Disease, Keck School of Medicine, University of Southern California, Los Angeles CA
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Susukida T, Sekine S, Nozaki M, Tokizono M, Ito K. Prediction of the Clinical Risk of Drug-Induced Cholestatic Liver Injury Using an In Vitro Sandwich Cultured Hepatocyte Assay. Drug Metab Dispos 2015; 43:1760-8. [PMID: 26329788 DOI: 10.1124/dmd.115.065425] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Accepted: 08/31/2015] [Indexed: 12/12/2022] Open
Abstract
Drug-induced liver injury (DILI) is of concern to the pharmaceutical industry, and reliable preclinical screens are required. Previously, we established an in vitro bile acid-dependent hepatotoxicity assay that mimics cholestatic DILI in vivo. Here, we confirmed that this assay can predict cholestatic DILI in clinical situations by comparing in vitro cytotoxicity data with in vivo risk. For 38 drugs, the frequencies of abnormal increases in serum alkaline phosphatase (ALP), transaminases, gamma glutamyltranspeptidase (γGT), and bilirubin were collected from interview forms. Drugs with frequencies of serum marker increases higher than 1% were classified as high DILI risk compounds. In vitro cytotoxicity was assessed by monitoring lactate dehydrogenase release from rat and human sandwich-cultured hepatocytes (SCRHs and SCHHs) incubated with the test drugs (50 μM) for 24 hours in the absence or presence of a bile acids mixture. Receiver operating characteristic analyses gave optimal cutoff toxicity values of 19.5% and 9.2% for ALP and transaminases in SCRHs, respectively. Using this cutoff, high- and low-risk drugs were separated with 65.4-78.6% sensitivity and 66.7-79.2% specificity. Good separation was also achieved using SCHHs. In conclusion, cholestatic DILI risk can be successfully predicted using a sandwich-cultured hepatocyte-based assay.
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Affiliation(s)
- Takeshi Susukida
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba, Japan
| | - Shuichi Sekine
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba, Japan
| | - Mayuka Nozaki
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba, Japan
| | - Mayuko Tokizono
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba, Japan
| | - Kousei Ito
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba, Japan
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Chen M, Suzuki A, Borlak J, Andrade RJ, Lucena MI. Drug-induced liver injury: Interactions between drug properties and host factors. J Hepatol 2015; 63:503-14. [PMID: 25912521 DOI: 10.1016/j.jhep.2015.04.016] [Citation(s) in RCA: 262] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Revised: 04/01/2015] [Accepted: 04/07/2015] [Indexed: 12/13/2022]
Abstract
Idiosyncratic drug-induced liver injury (DILI) is a common cause for drug withdrawal from the market and although infrequent, DILI can result in serious clinical outcomes including acute liver failure and the need for liver transplantation. Eliminating the iatrogenic "harm" caused by a therapeutic intent is a priority in patient care. However, identifying culprit drugs and individuals at risk for DILI remains challenging. Apart from genetic factors predisposing individuals at risk, the role of the drugs' physicochemical and toxicological properties and their interactions with host and environmental factors need to be considered. The influence of these factors on mechanisms involved in DILI is multi-layered. In this review, we summarize current knowledge on 1) drug properties associated with hepatotoxicity, 2) host factors considered to modify an individuals' risk for DILI and clinical phenotypes, and 3) drug-host interactions. We aim at clarifying knowledge gaps needed to be filled in as to improve risk stratification in patient care. We therefore broadly discuss relevant areas of future research. Emerging insight will stimulate new investigational approaches to facilitate the discovery of clinical DILI risk modifiers in the context of disease complexity and associated interactions with drug properties, and hence will be able to move towards safety personalized medicine.
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Affiliation(s)
- Minjun Chen
- Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, United States
| | - Ayako Suzuki
- Gastroenterology, Central Arkansas Veterans Healthcare System, Little Rock, AR, United States; Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Jürgen Borlak
- Center of Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany
| | - Raúl J Andrade
- Unidad de Gestión Clínica de Enfermedades Digestivas, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
| | - M Isabel Lucena
- Unidad de Gestión Clínica de Enfermedades Digestivas, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
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Li AP. Evaluation of Adverse Drug Properties with Cryopreserved Human Hepatocytes and the Integrated Discrete Multiple Organ Co-culture (IdMOC(TM)) System. Toxicol Res 2015; 31:137-49. [PMID: 26191380 PMCID: PMC4505344 DOI: 10.5487/tr.2015.31.2.137] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Revised: 03/23/2015] [Accepted: 04/02/2015] [Indexed: 12/26/2022] Open
Abstract
Human hepatocytes, with complete hepatic metabolizing enzymes, transporters and cofactors, represent the gold standard for in vitro evaluation of drug metabolism, drug-drug interactions, and hepatotoxicity. Successful cryopreservation of human hepatocytes enables this experimental system to be used routinely. The use of human hepatocytes to evaluate two major adverse drug properties: drug-drug interactions and hepatotoxicity, are summarized in this review. The application of human hepatocytes in metabolism-based drug-drug interaction includes metabolite profiling, pathway identification, P450 inhibition, P450 induction, and uptake and efflux transporter inhibition. The application of human hepatocytes in toxicity evaluation includes in vitro hepatotoxicity and metabolism-based drug toxicity determination. A novel system, the Integrated Discrete Multiple Organ Co-culture (IdMOC) which allows the evaluation of nonhepatic toxicity in the presence of hepatic metabolism, is described.
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Affiliation(s)
- Albert P Li
- In Vitro ADMET Laboratories LLC, 9221 Rumsey Road Suite 8, Columbia, MD 21045
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27
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Watkins PB, Merz M, Avigan MI, Kaplowitz N, Regev A, Senior JR. The clinical liver safety assessment best practices workshop: rationale, goals, accomplishments and the future. Drug Saf 2015; 37 Suppl 1:S1-7. [PMID: 25352323 PMCID: PMC4212148 DOI: 10.1007/s40264-014-0181-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Paul B Watkins
- The Hamner-University of North Carolina Institute for Drug Safety Sciences, 6 Davis Drive, PO Box 12137, Research Triangle Park, NC, 27709, USA,
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Žitnik M, Zupan B. Matrix factorization-based data fusion for drug-induced liver injury prediction. ACTA ACUST UNITED AC 2014. [DOI: 10.4161/sysb.29072] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Wang Y, Chen T, Tong W. miRNAs and their application in drug-induced liver injury. Biomark Med 2014; 8:161-72. [PMID: 24521012 DOI: 10.2217/bmm.13.147] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The complex miRNA regulatory network plays an important role in diverse biological activities of physiopathological processes. In addition to the discovery of and research on the extracellular miRNAs detected in multiple biofluids, the properties of tissue specificity and high stability underlie the great potential of these small miRNAs to serve as translational biomarkers for various diseases in the clinical setting, including in drug-induced liver injury. In this review, we describe the major technologies currently used and challenges in miRNA measurement and provide information on major bioinformatics resources available for current miRNA research. We also discuss novel findings in liver disease and highlight the potential of miRNAs for clinical and basic research as translational biomarkers for drug-induced liver injury.
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Affiliation(s)
- Yuping Wang
- Division of Bioinformatics & Biostatistics, National Center for Toxicological Research, US FDA, 3900 NCTR Road, Jefferson, AR 72079, USA
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Sumie S, Kawaguchi T, Kawaguchi A, Kuromatsu R, Nakano M, Satani M, Yamada S, Okamura S, Yonezawa Y, Kakuma T, Torimura T, Sata M. Effect of pioglitazone on outcome following curative treatment for hepatocellular carcinoma in patients with hepatitis C virus infection: A prospective study. Mol Clin Oncol 2014; 3:115-120. [PMID: 25469280 DOI: 10.3892/mco.2014.435] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Accepted: 09/01/2014] [Indexed: 12/19/2022] Open
Abstract
Pioglitazone is an insulin sensitizer used for the treatment of diabetes mellitus (DM). DM with insulin resistance is a risk factor for hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV) infection. We aimed to investigate the effects of pioglitazone on HCC recurrence following treatment in HCV-infected patients. Between 2009 and 2011, 85 HCV-infected HCC patients who underwent curative treatment were enrolled in this prospective study. Among 45 patients with type 2 DM, 27 were administered pioglitazone (pioglitazone group) following treatment. The remaining 58 patients were assigned to the control group. The primary outcome was recurrence-free survival. Changes in insulin resistance and serum adiponectin levels resulting from pioglitazone treatment were also assessed. In the whole analysis (n=85), no significant difference in recurrence-free survival was observed between the pioglitazone and control groups. However, in a spline model analysis of DM patients, a decreased risk of HCC recurrence was associated with increased body weight in patients with a body mass index (BMI) ≥23; this association became significant at BMI ≥24 (hazard ratio=0.17; 95% confidence interval: 0.03-0.95). In addition, significantly decreased homeostasis model assessment for insulin resistance values (P=0.002) and significantly increased serum high-molecular-weight adiponectin levels (P<0.001) were observed following pioglitazone treatment. Although pioglitazone did not suppress HCC recurrence in the whole analysis, it inhibited HCC recurrence in overweight HCV-infected diabetic patients. Moreover, pioglitazone improved insulin resistance and adipocytokine levels. Thus, pioglitazone may suppress HCC recurrence, which is associated with glucose and fat metabolism disorders.
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Affiliation(s)
- Shuji Sumie
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Atsushi Kawaguchi
- Biostatistics Center, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Ryoko Kuromatsu
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Masahito Nakano
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Manabu Satani
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Shingo Yamada
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Shusuke Okamura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Yuko Yonezawa
- Graduate School of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Tatsuyuki Kakuma
- Biostatistics Center, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Takuji Torimura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Michio Sata
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
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Vuppalanchi R, Gotur R, Reddy KR, Fontana RJ, Ghabril M, Kosinski AS, Gu J, Serrano J, Chalasani N. Relationship between characteristics of medications and drug-induced liver disease phenotype and outcome. Clin Gastroenterol Hepatol 2014; 12:1550-5. [PMID: 24362054 PMCID: PMC4065228 DOI: 10.1016/j.cgh.2013.12.016] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2013] [Revised: 12/11/2013] [Accepted: 12/12/2013] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS It is not known whether specific characteristics of medication are associated with type of drug-induced liver injury (DILI) or outcome. We examined the relationships among select characteristics of medications and DILI phenotype and outcome. METHODS We analyzed 383 cases of DILI caused by a single orally administered prescription agent from the DILI Network Prospective Study with causalities of definite, highly likely, or probable. Relationship of daily dosage (≥50 mg vs ≤49 mg), preponderance of hepatic metabolism (≥50% vs <50%), or Biopharmaceutics Drug Disposition Classification System (BDDCS) class (1-4, based on solubility and metabolism of the drug) were compared with clinical characteristics and outcomes. RESULTS Compared with cases of DILI in the ≤49 mg/day group, those associated with daily dosages ≥50 mg had shorter latency (median, 38 days vs 56 days; P = .03) and a different biochemical pattern of liver injury (P = .04); no differences in recovery, severity, or outcome were observed. Patients with DILI caused by medications with or without preponderant hepatic metabolism did not differ in clinical characteristics or outcomes. Compared with other classes of BDDCS, DILI caused by BDDCS class 1 medications had significantly longer latency (P < .001) and greater proportion of hepatocellular injury (P = .001). However, peak liver biochemical values and patients' time to recovery, disease severity, and outcomes did not differ among the 4 BDDCS classes. CONCLUSIONS Characteristics of medications (dosage, hepatic metabolism, and solubility) are associated with features of DILI such as latency and pattern of liver injury, but not with recovery, severity, or outcome.
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Affiliation(s)
- Raj Vuppalanchi
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Raghavender Gotur
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - K Rajender Reddy
- Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Robert J Fontana
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan
| | - Marwan Ghabril
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | | | - Jiezhun Gu
- Duke Clinical Research Institute, Durham, North Carolina
| | - Jose Serrano
- Liver Disease Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Naga Chalasani
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
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Lewis JH. Drug-induced liver injury, dosage, and drug disposition: is idiosyncrasy really unpredictable? Clin Gastroenterol Hepatol 2014; 12:1556-61. [PMID: 24530601 DOI: 10.1016/j.cgh.2014.02.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Revised: 02/05/2014] [Accepted: 02/05/2014] [Indexed: 02/07/2023]
Affiliation(s)
- James H Lewis
- Department of Medicine, Division of Gastroenterology and Hepatology, Georgetown University Medical Center, Washington, DC
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Steinebrunner N, Mogler C, Vittas S, Hoyler B, Sandig C, Stremmel W, Eisenbach C. Pharmacologic cholinesterase inhibition improves survival in acetaminophen-induced acute liver failure in the mouse. BMC Gastroenterol 2014; 14:148. [PMID: 25139304 PMCID: PMC4236504 DOI: 10.1186/1471-230x-14-148] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Accepted: 08/13/2014] [Indexed: 12/27/2022] Open
Abstract
Background Acetaminophen (APAP) is one of the most widely used analgesic and antipyretic pharmaceutical substances in the world and accounts for most cases of drug induced liver injury resulting in acute liver failure. Acute liver failure initiates a sterile inflammatory response with release of cytokines and innate immune cell infiltration in the liver. This study investigates, whether pharmacologic acetylcholinesterase inhibition with neostigmine diminishes liver damage in acute liver failure via the cholinergic anti-inflammatory pathway. Methods Acute liver failure was induced in BALB/c mice by a toxic dose of acetaminophen (APAP). Neostigmine and/or N-acetyl-cysteine (NAC) were applied therapeutically at set time points and the survival was investigated. Liver damage was assessed by serum parameters, histopathology and serum cytokine assays 12 h after initiation of acute liver failure. Results Serum parameters, histopathology and serum cytokine assays showed pronounced features of acute liver failure 12 h after application of acetaminophen (APAP). Neostigmine treatment led to significant reduction of serum liver enzymes (LDH (47,147 ± 12,726 IU/l vs. 15,822 ± 10,629 IU/l, p = 0.0014) and ALT (18,048 ± 4,287 IU/l vs. 7,585 ± 5,336 IU/l, p = 0.0013), APAP-alone-treated mice vs. APAP + neostigmine-treated mice), inflammatory cytokine levels (IL-1β (147 ± 19 vs. 110 ± 25, p = 0.0138) and TNF-α (184 ± 23 vs. 130 ± 33, p = 0.0086), APAP-alone-treated mice vs. APAP + neostigmine-treated mice) and histopathological signs of damage. Animals treated with NAC in combination with the peripheral cholinesterase inhibitor neostigmine showed prolonged survival and improved outcome. Conclusions Neostigmine is an acetylcholinesterase inhibitor that ameliorates the effects of APAP-induced acute liver failure in the mouse and therefore may provide new treatment options for affected patients.
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Affiliation(s)
- Niels Steinebrunner
- Department of Gastroenterology, Hepatology, Intoxications and Infectious Diseases, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
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A testing strategy to predict risk for drug-induced liver injury in humans using high-content screen assays and the 'rule-of-two' model. Arch Toxicol 2014; 88:1439-49. [PMID: 24958025 DOI: 10.1007/s00204-014-1276-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Accepted: 05/19/2014] [Indexed: 12/13/2022]
Abstract
Drug-induced liver injury (DILI) is a major cause of drug failures in both the preclinical and clinical phase. Consequently, improving prediction of DILI at an early stage of drug discovery will reduce the potential failures in the subsequent drug development program. In this regard, high-content screening (HCS) assays are considered as a promising strategy for the study of DILI; however, the predictive performance of HCS assays is frequently insufficient. In the present study, a new testing strategy was developed to improve DILI prediction by employing in vitro assays that was combined with the RO2 model (i.e., 'rule-of-two' defined by daily dose ≥100 mg/day & logP ≥3). The RO2 model was derived from the observation that high daily doses and lipophilicity of an oral medication were associated with significant DILI risk in humans. In the developed testing strategy, the RO2 model was used for the rational selection of candidates for HCS assays, and only the negatives predicted by the RO2 model were further investigated by HCS. Subsequently, the effects of drug treatment on cell loss, nuclear size, DNA damage/fragmentation, apoptosis, lysosomal mass, mitochondrial membrane potential, and steatosis were studied in cultures of primary rat hepatocytes. Using a set of 70 drugs with clear evidence of clinically relevant DILI, the testing strategy improved the accuracies by 10 % and reduced the number of drugs requiring experimental assessment by approximately 20 %, as compared to the HCS assay alone. Moreover, the testing strategy was further validated by including published data (Cosgrove et al. in Toxicol Appl Pharmacol 237:317-330, 2009) on drug-cytokine-induced hepatotoxicity, which improved the accuracies by 7 %. Taken collectively, the proposed testing strategy can significantly improve the prediction of in vitro assays for detecting DILI liability in an early drug discovery phase.
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Chalhoub WM, Sliman KD, Arumuganathan M, Lewis JH. Drug-induced liver injury: what was new in 2013? Expert Opin Drug Metab Toxicol 2014; 10:959-80. [PMID: 24746272 DOI: 10.1517/17425255.2014.909408] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION The year 2013 continued to highlight numerous aspects of drug-induced liver injury (DILI), with new information communicated via > 1500 publications. New reports of DILI were described and FDA warnings and alerts were issued for a number of products, emphasizing the risks related to hepatotoxicity. AREAS COVERED We provide a summary of the year's published reports of new causes of DILI, along with reviews and reports of established hepatotoxins, new and expanded DILI registries and the continuing emphasis placed on genetic and other risk factors. Several new analyses of data generated from the US DILI Network are included. EXPERT OPINION The clinical usefulness of pharmacogenetic testing remains to be determined; the number of patients who must be tested is large and the overall risk of DILI is quite small. The role that dose and hepatic metabolism play in causing idiosyncratic DILI was reviewed; daily doses > 50 - 100 mg of medications with high lipophilicity appear to be most predictive of severe DILI, but not in all cases. Restricting access to paracetamol in certain parts of the UK continues to demonstrate a successful reduction in the number of acute liver failure cases and patients listed for liver transplant.
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Affiliation(s)
- Walid M Chalhoub
- Georgetown University Hospital, Department of Medicine, Division of Gastroenterology, Hepatology Section , 3800 Reservoir Road, NW, Washington, DC 20007 , USA
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Fontana RJ. Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives. Gastroenterology 2014; 146:914-28. [PMID: 24389305 PMCID: PMC4031195 DOI: 10.1053/j.gastro.2013.12.032] [Citation(s) in RCA: 203] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Revised: 12/03/2013] [Accepted: 12/11/2013] [Indexed: 12/13/2022]
Abstract
Idiosyncratic drug-induced liver injury (DILI) is a rare disease that develops independently of drug dose, route, or duration of administration. Furthermore, idiosyncratic DILI is not a single disease entity but rather a spectrum of rare diseases with varying clinical, histological, and laboratory features. The pathogenesis of DILI is not fully understood. Standardization of the DILI nomenclature and methods to assess causality, along with the information provided by the LiverTox Web site, will harmonize and accelerate research on DILI. Studies of new serum biomarkers such as glutamate dehydrogenase, high mobility group box protein 1, and microRNA-122 could provide information for use in diagnosis and prognosis and provide important insights into the mechanisms of the pathogenesis of DILI. Single nucleotide polymorphisms in the HLA region have been associated with idiosyncratic hepatotoxicity attributed to flucloxacillin, ximelagatran, lapatinib, and amoxicillin-clavulanate. However, genome-wide association studies of pooled cases have not associated any genetic factors with idiosyncratic DILI. Whole genome and whole exome sequencing analyses are under way to study cases of DILI attributed to a single medication. Serum proteomic, transcriptome, and metabolome as well as intestinal microbiome analyses will increase our understanding of the mechanisms of this disorder. Further improvements to in vitro and in vivo test systems should advance our understanding of the causes, risk factors, and mechanisms of idiosyncratic DILI.
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Abstract
The accuracy of preclinical safety evaluation to predict human toxicity is hindered by species difference in drug metabolism and toxic mechanism between human and nonhuman animals. In vitro human-based experimental systems allowing the assessment of human-specific drug properties represent a logical and practical approach to provide human-specific information. An advantage of in vitro approaches is that they require only limited amounts of time and resources, and, most importantly, do not invoke harm to human patients. Human hepatocytes, with complete hepatic metabolizing enzymes, transporters and cofactors, represent a practical and useful experimental system to assess drug metabolism. The use of human hepatocytes to evaluate two major adverse drug properties, drug–drug interactions and hepatotoxicity, are reviewed. The application of human hepatocytes in metabolism-based drug–drug interactions includes metabolite profiling, pathway identification, CYP450 inhibition, CYP450 induction, and uptake and efflux transporter inhibition. The application of human hepatocytes in toxicity evaluation includes in vitro hepatotoxicity and metabolism-based drug toxicity determination. Correlation of drug toxicity with proteomics and genomics data may allow the discovery of clinical biomarkers for early detection of liver toxicity.
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Affiliation(s)
- Albert P Li
- In Vitro ADMET Laboratories LLC, 9221 Rumsey Road Suite 8, Columbia, MD 21045, USA
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Chen M, Hong H, Fang H, Kelly R, Zhou G, Borlak J, Tong W. Quantitative Structure-Activity Relationship Models for Predicting Drug-Induced Liver Injury Based on FDA-Approved Drug Labeling Annotation and Using a Large Collection of Drugs. Toxicol Sci 2013; 136:242-9. [DOI: 10.1093/toxsci/kft189] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
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