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Bock K, Engel B, Jaeckel E, Wedemeyer H, Mederacke I, Mederacke YS. LKM Immunofluorescence Is Associated with DILI, Especially after Metamizole Intake. Dig Dis 2025:1-11. [PMID: 40159290 PMCID: PMC12060832 DOI: 10.1159/000545507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Accepted: 03/21/2025] [Indexed: 04/02/2025]
Abstract
INTRODUCTION Drug-induced liver injury (DILI) is a rare but potentially serious clinical condition. One phenotype of DILI is termed drug-induced autoimmune like hepatitis (DI-ALH) that presents with laboratory and histological features indistinguishable from autoimmune hepatitis. Liver kidney microsomal antibodies (LKM-antibodies) are common in the diagnosis of AIH but were also described to be associated with halothane-induced DILI. Also, the antigens of anti-LKM-1 and anti-LKM-2 belong to the cytochrome P450 enzyme family that is involved in the metabolism of various drugs. Therefore, we aimed to study the impact of LKM-antibodies in the diagnostic work-up of suspected DILI in a large cohort of patients with liver injury in a tertiary care centre. METHODS We screened a large single centre hospital database and retrospectively identified 63,300 cases with liver injury as defined: AST or ALT >3 upper limit of normal (ULN) or AP or TBI >2 ULN. Of those, 82 cases with LKM immunofluorescence positivity (titre ≥1: 160) were identified, of which 64 patients fulfilled the inclusion criteria for this study. RESULTS Positive LKM immunofluorescence was associated with drug-induced autoimmune-like hepatitis (DI-ALH). Metamizole association was identified in half of the patients (n = 33, 52%). Eight patients with metamizole associated DI-ALHs required liver transplantation and 1 patient died. CONCLUSION DI-ALH, especially after metamizole administration, can be a reason for a positivity in LKM immunofluorescence tests. Metamizole DI-ALH has a high liver-related mortality.
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Affiliation(s)
- Kilian Bock
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover, Germany,
| | - Bastian Engel
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover, Germany
| | - Elmar Jaeckel
- Ajmera Transplant Centre, Toronto General Hospital, UHN, University of Toronto, Toronto, Ontario, Canada
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover, Germany
| | - Ingmar Mederacke
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover, Germany
| | - Young-Seon Mederacke
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover, Germany
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Nikolajevic N, Nikolajevic M, Pantic I, Korica B, Kotseva M, Alempijevic T, Jevtic D, Madrid CI, Dumic I. Drug-Induced Liver Injury Due to Doxycycline: A Case Report and Review of Literature. Cureus 2024; 16:e59687. [PMID: 38836151 PMCID: PMC11150051 DOI: 10.7759/cureus.59687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/03/2024] [Indexed: 06/06/2024] Open
Abstract
Antibiotics are among the most common causes of drug-induced liver injury worldwide. Amoxicillin/clavulanic acid and nitrofurantoin are the most common culprits while tetracyclines are a rare cause of liver injury. Among tetracyclines, minocycline has been reported more frequently than doxycycline, which is an extremely rare cause of drug-induced liver injury. We present a healthy 28-year-old male patient from rural United States who was taking doxycycline for Lyme disease. After five days of therapy, he developed nausea, vomiting, fatigue, and significant transaminitis consistent with a hepatocellular pattern of liver injury. After a thorough workup which ruled out other causes such as infection, autoimmune diseases, liver malignancy, and vascular, structural, and metabolic disorders, his liver injury was attributed to doxycycline. We reached the diagnosis also by demonstrating a consistent temporal association between doxycycline intake and liver injury and the patient recovered completely with the cessation of doxycycline. Recognition of doxycycline as a cause of drug-induced liver injury should be considered in patients utilizing this antibiotic. Doxycycline, unlike minocycline, has a short latency period. Early recognition and discontinuation of doxycycline in our patient resulted in the complete resolution of symptoms and transaminitis preventing further morbidity and mortality.
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Affiliation(s)
- Nikola Nikolajevic
- Internal Medicine, University of Belgrade, Faculty of Medicine, Belgrade, SRB
| | - Milan Nikolajevic
- Internal Medicine, University of Belgrade, Faculty of Medicine, Belgrade, SRB
| | - Ivana Pantic
- Gastroenterology and Hepatology, Clinic for Gastroenterology, University Clinical Center of Serbia, Belgrade, SRB
| | - Bojan Korica
- Gastroenterology and Hepatology, Clinic for Gastroenterology, University Clinical Center of Serbia, Belgrade, SRB
| | | | - Tamara Alempijevic
- Gastroenterology and Hepatology, Clinic for Gastroenterology, University Clinical Center of Serbia, Belgrade, SRB
| | - Dorde Jevtic
- Internal Medicine, NYC Health + Hospitals/Elmhurst, Queens, USA
| | | | - Igor Dumic
- Hospital Medicine, Mayo Clinic Health System, Eau Claire, USA
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Nastasio S, Mosca A, Alterio T, Sciveres M, Maggiore G. Juvenile Autoimmune Hepatitis: Recent Advances in Diagnosis, Management and Long-Term Outcome. Diagnostics (Basel) 2023; 13:2753. [PMID: 37685291 PMCID: PMC10486972 DOI: 10.3390/diagnostics13172753] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/11/2023] [Accepted: 08/13/2023] [Indexed: 09/10/2023] Open
Abstract
Juvenile autoimmune hepatitis (JAIH) is severe immune-mediated necro-inflammatory disease of the liver with spontaneous progression to cirrhosis and liver failure if left untreated. The diagnosis is based on the combination of clinical, laboratory and histological findings. Prothrombin ratio is a useful prognostic factor to identify patients who will most likely require a liver transplant by adolescence or early adulthood. JAIH treatment consists of immune suppression and should be started promptly at diagnosis to halt inflammatory liver damage and ultimately prevent fibrosis and progression to end-stage liver disease. The risk of relapse is high especially in the setting of poor treatment compliance. Recent evidence however suggests that treatment discontinuation is possible after a prolonged period of normal aminotransferase activity without the need for liver biopsy prior to withdrawal.
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Affiliation(s)
- Silvia Nastasio
- Division of Gastroenterology, Hepatology & Nutrition, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA;
| | - Antonella Mosca
- Hepatogastroenterology, Rehabilitative Nutrition, Digestive Endoscopy and Liver Transplant Unit, ERN RARE LIVER, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (A.M.); (T.A.)
| | - Tommaso Alterio
- Hepatogastroenterology, Rehabilitative Nutrition, Digestive Endoscopy and Liver Transplant Unit, ERN RARE LIVER, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (A.M.); (T.A.)
| | - Marco Sciveres
- Pediatric Department and Transplantation, ISMETT, 90133 Palermo, Italy;
| | - Giuseppe Maggiore
- Hepatogastroenterology, Rehabilitative Nutrition, Digestive Endoscopy and Liver Transplant Unit, ERN RARE LIVER, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (A.M.); (T.A.)
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4
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Gerussi A, Halliday N, Carbone M, Invernizzi P, Thorburn D. Open challenges in the management of autoimmune hepatitis. Minerva Gastroenterol (Torino) 2023; 69:61-83. [PMID: 33267568 DOI: 10.23736/s2724-5895.20.02805-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/02/2023]
Abstract
Autoimmune hepatitis (AIH) is a rare autoimmune disease of the liver with many open questions as regards its etiopathogenesis, natural history and clinical management. The classical picture of AIH is chronic hepatitis with fluctuating elevation of serum transaminases and Immunoglobulin G levels, the presence of circulating autoantibodies and typical histological features. However, atypical presentations do occur and are not well captured by current diagnostic scores, with important consequences in terms of missed diagnoses and delayed treatments. AIH is treated with corticosteroids and immunosuppressive drugs but up to 40% of patients do not achieve full biochemical response and are at risk of progressing to cirrhosis and liver failure. Moreover, standard therapies are associated by significant side-effects which may impair the quality of life of patients living with AIH. However, advances in the understanding of the underlying immunology of AIH is raising the prospect of novel therapies and optimization of existing therapeutic approaches to reduce side-effect burdens and potentially restore immunological tolerance. In this review we outlined the clinical characteristics, etiopathogenesis and management of AIH and current challenges in the diagnosis and management of AIH and provided evidence underlying the evolution of diagnostic and clinical management protocols.
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Affiliation(s)
- Alessio Gerussi
- Division of Gastroenterology, Department of Medicine and Surgery, Center for Autoimmune Liver Diseases, University of Milano-Bicocca, Monza, Monza-Brianza, Italy - .,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Monza-Brianza, Italy - .,Ancient DNA Lab Dan David Center for Human Evolution and Biohistory Research, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel -
| | - Neil Halliday
- Institute for Liver and Digestive Health, University College London, London, UK
| | - Marco Carbone
- Division of Gastroenterology, Department of Medicine and Surgery, Center for Autoimmune Liver Diseases, University of Milano-Bicocca, Monza, Monza-Brianza, Italy.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Monza-Brianza, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology, Department of Medicine and Surgery, Center for Autoimmune Liver Diseases, University of Milano-Bicocca, Monza, Monza-Brianza, Italy.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Monza-Brianza, Italy
| | - Douglas Thorburn
- Institute for Liver and Digestive Health, University College London, London, UK
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5
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Tan CK, Ho D, Wang LM, Kumar R. Drug-induced autoimmune hepatitis: A minireview. World J Gastroenterol 2022; 28:2654-2666. [PMID: 35979160 PMCID: PMC9260871 DOI: 10.3748/wjg.v28.i24.2654] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 09/15/2021] [Accepted: 05/14/2022] [Indexed: 02/06/2023] Open
Abstract
Drug-induced autoimmune hepatitis (DIAIH) is a specific phenotype of drug-induced liver injury that may lead to the devastating outcome of acute liver failure requiring liver transplantation. Drugs implicated in DIAIH include antimicrobials such as nitrofurantoin and minocycline, non-steroidal anti-inflammatory drugs, statins as well as anti-tumor necrosis agents. The clinical features of drug-induced liver injury are indistinguishable from idiopathic autoimmune hepatitis (AIH) as both may have positive AIH-related autoantibodies, elevated immunoglobulin G, as well as similar histopathological findings. In patients who show no clinical improvement, or there is progressive liver injury despite cessation of the suspected drug, a liver biopsy should be considered, whereby the presence of advance fibrosis on histology favors the diagnosis of idiopathic AIH. Empirical treatment with corticosteroids may be required in patients with non-resolving liver injury. A typical clinical scenario supportive of DIAIH includes a history of drug exposure with spontaneous resolution of liver injury after drug withdrawal and the absence of relapse after rapid steroid taper. In this article we report two cases of DIAIH secondary to Sorafenib and Atorvastatin along with a review of currently available literature. Early identification and treatment often lead to a favorable outcome in DIAIH.
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Affiliation(s)
- Chin Kimg Tan
- Gastroenterology and Hepatology, Changi General Hospital, Singapore 529889, Singapore
- Medicine Academic Clinical Programme, SingHealth Duke-NUS Academic Medical Centre, Singapore 529889, Singapore
| | - Danielle Ho
- Gastroenterology and Hepatology, Changi General Hospital, Singapore 529889, Singapore
| | - Lai Mun Wang
- Section of Pathology, Department of Laboratory Medicine, Changi General Hospital, Singapore 529889, Singapore
- Pathology Academic Clinical Programme, SingHealth Duke-NUS Academic Medical Centre, Singapore 529889, Singapore
| | - Rahul Kumar
- Gastroenterology and Hepatology, Changi General Hospital, Singapore 529889, Singapore
- Medicine Academic Clinical Programme, SingHealth Duke-NUS Academic Medical Centre, Singapore 529889, Singapore
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Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D. Autoimmune Hepatitis: Serum Autoantibodies in Clinical Practice. Clin Rev Allergy Immunol 2022; 63:124-137. [PMID: 34491531 PMCID: PMC9464171 DOI: 10.1007/s12016-021-08888-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/24/2021] [Indexed: 01/13/2023]
Abstract
Circulating autoantibodies are a key diagnostic tool in autoimmune hepatitis (AIH), being positive in 95% of the cases if tested according to dedicated guidelines issued by the International Autoimmune Hepatitis Group. They also allow the distinction between type 1 AIH, characterized by positive anti-nuclear and/or anti-smooth muscle antibody, and type 2 AIH, characterized by positive anti-liver kidney microsomal type 1 and/or anti-liver cytosol type 1 antibody. Anti-soluble liver antigen is the only AIH-specific autoantibody, and is found in 20-30% of both type 1 and type 2 AIH. Anti-neutrophil cytoplasmic antibody is frequently positive in type 1 AIH, being associated also with inflammatory bowel disease and with primary/autoimmune sclerosing cholangitis. The reference method for autoantibody testing remains indirect immunofluorescence on triple tissue (rodent liver, kidney and stomach), allowing both the detection of the majority of liver-relevant reactivities, including those autoantibodies whose molecular target antigens are unknown. Of note, the current knowledge of the clinical significance of autoantibodies relies on studies based on this technique. However, immunofluorescence requires trained laboratory personnel, is observer-dependent, and lacks standardization, leading to ongoing attempts at replacing this method with automated assays, the sensitivity, and specificity of which, however, require further studies before they can be used as a reliable alternative to immunofluorescence; currently, they may be used as complementary to immunofluorescence.
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Affiliation(s)
- Benedetta Terziroli Beretta-Piccoli
- grid.29078.340000 0001 2203 2861Epatocentro Ticino & Facoltà Di Scienze Biomediche, Università Della Svizzera Italiana, Lugano, Switzerland ,grid.29078.340000 0001 2203 2861Institute for Research in Biomedicine, Bellinzona, Switzerland ,grid.46699.340000 0004 0391 9020King’s College London Faculty of Life Sciences &, Medicine At King’s College Hospital, London, UK
| | - Giorgina Mieli-Vergani
- grid.46699.340000 0004 0391 9020King’s College London Faculty of Life Sciences &, Medicine At King’s College Hospital, London, UK ,grid.46699.340000 0004 0391 9020Paediatric Liver, GI and Nutrition Centre, MowatLabs, King’s College Hospital, London, UK
| | - Diego Vergani
- grid.46699.340000 0004 0391 9020King’s College London Faculty of Life Sciences &, Medicine At King’s College Hospital, London, UK ,grid.46699.340000 0004 0391 9020Institute of Liver Studies, MowatLabs, King’s College Hospital, London, UK
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7
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Zachou K, Arvaniti P, Lyberopoulou A, Dalekos GN. Impact of genetic and environmental factors on autoimmune hepatitis. J Transl Autoimmun 2021; 4:100125. [PMID: 34622188 PMCID: PMC8479787 DOI: 10.1016/j.jtauto.2021.100125] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Accepted: 09/20/2021] [Indexed: 02/07/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic non-resolving liver disease characterized by diffuse hypergammaglobulinemia, the presence of autoantibodies and characteristic histological findings. The disease can have catastrophic outcome with the development of end-stage liver disease if misdiagnosed/undiagnosed and left untreated. AIH pathogenesis remains obscure and the main hypothesis supports its development in genetically predisposed individuals after being exposed to certain environmental triggers. Genetic predisposition is linked to the presence of certain HLA alleles, mainly HLA-DR3 and HLA-DR4. However, a wide number of non-HLA epitopes have also been associated with the disease although data vary significantly among different ethnic groups. Therefore, it is likely that epigenetic alterations may also play a crucial role in disease's pathogenesis, although not yet extensively studied. The aim of this review was to summarize the genetic and environmental factors that have been associated with AIH, but also to open new insights towards the role of epigenetic modifications in the etiology of the disease.
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Affiliation(s)
- Kalliopi Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center in Autoimmune Liver Diseases, University Hospital of Larissa, Larissa, Greece
| | - Pinelopi Arvaniti
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center in Autoimmune Liver Diseases, University Hospital of Larissa, Larissa, Greece
| | - Aggeliki Lyberopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center in Autoimmune Liver Diseases, University Hospital of Larissa, Larissa, Greece
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center in Autoimmune Liver Diseases, University Hospital of Larissa, Larissa, Greece
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8
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Guengerich FP. A history of the roles of cytochrome P450 enzymes in the toxicity of drugs. Toxicol Res 2021; 37:1-23. [PMID: 32837681 PMCID: PMC7431904 DOI: 10.1007/s43188-020-00056-z] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 05/22/2020] [Accepted: 06/11/2020] [Indexed: 02/07/2023] Open
Abstract
The history of drug metabolism began in the 19th Century and developed slowly. In the mid-20th Century the relationship between drug metabolism and toxicity became appreciated, and the roles of cytochrome P450 (P450) enzymes began to be defined in the 1960s. Today we understand much about the metabolism of drugs and many aspects of safety assessment in the context of a relatively small number of human P450s. P450s affect drug toxicity mainly by either reducing exposure to the parent molecule or, in some cases, by converting the drug into a toxic entity. Some of the factors involved are enzyme induction, enzyme inhibition (both reversible and irreversible), and pharmacogenetics. Issues related to drug toxicity include drug-drug interactions, drug-food interactions, and the roles of chemical moieties of drug candidates in drug discovery and development. The maturation of the field of P450 and drug toxicity has been facilitated by advances in analytical chemistry, computational capability, biochemistry and enzymology, and molecular and cell biology. Problems still arise with P450s and drug toxicity in drug discovery and development, and in the pharmaceutical industry the interaction of scientists in medicinal chemistry, drug metabolism, and safety assessment is critical for success.
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Affiliation(s)
- F. Peter Guengerich
- Department of Biochemistry, Vanderbilt University School of Medicine, 638B Robinson Research Building, 2200 Pierce Avenue, Nashville, TN 37232-0146 USA
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9
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Kwon D, Kim SM, Correia MA. Cytochrome P450 endoplasmic reticulum-associated degradation (ERAD): therapeutic and pathophysiological implications. Acta Pharm Sin B 2020; 10:42-60. [PMID: 31993306 PMCID: PMC6976991 DOI: 10.1016/j.apsb.2019.11.002] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 10/30/2019] [Accepted: 10/31/2019] [Indexed: 02/07/2023] Open
Abstract
The hepatic endoplasmic reticulum (ER)-anchored cytochromes P450 (P450s) are mixed-function oxidases engaged in the biotransformation of physiologically relevant endobiotics as well as of myriad xenobiotics of therapeutic and environmental relevance. P450 ER-content and hence function is regulated by their coordinated hemoprotein syntheses and proteolytic turnover. Such P450 proteolytic turnover occurs through a process known as ER-associated degradation (ERAD) that involves ubiquitin-dependent proteasomal degradation (UPD) and/or autophagic-lysosomal degradation (ALD). Herein, on the basis of available literature reports and our own recent findings of in vitro as well as in vivo experimental studies, we discuss the therapeutic and pathophysiological implications of altered P450 ERAD and its plausible clinical relevance. We specifically (i) describe the P450 ERAD-machinery and how it may be repurposed for the generation of antigenic P450 peptides involved in P450 autoantibody pathogenesis in drug-induced acute hypersensitivity reactions and liver injury, or viral hepatitis; (ii) discuss the relevance of accelerated or disrupted P450-ERAD to the pharmacological and/or toxicological effects of clinically relevant P450 drug substrates; and (iii) detail the pathophysiological consequences of disrupted P450 ERAD, contributing to non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) under certain synergistic cellular conditions.
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Key Words
- 3MA, 3-methyladenine
- AAA, ATPases associated with various cellular activities
- ACC1, acetyl-CoA carboxylase 1
- ACC2, acetyl-CoA carboxylase 2
- ACHE, acetylcholinesterase
- ACOX1, acyl-CoA oxidase 1
- ALD, autophagic-lysosomal degradation
- AMPK1
- AP-1, activator protein 1
- ASK1, apoptosis signal-regulating kinase
- ATF2, activating transcription factor 2
- AdipoR1, gene of adiponectin receptor 1
- Atg14, autophagy-related 14
- CBZ, carbamazepine
- CHIP E3 ubiquitin ligase
- CHIP, carboxy-terminus of Hsc70-interacting protein
- Cytochromes P450
- Endoplasmic reticulum-associated degradation
- FOXO, forkhead box O
- Fas, fatty acid synthase
- GAPDH, glyceraldehyde 3-phosphate dehydrogenase
- INH, isoniazid
- IRS1, insulin receptor substrate 1
- Il-1β, interleukin 1 β
- Il-6, interleukin 6
- Insig1, insulin-induced gene 1
- JNK1
- Lpl, lipoprotein lipase
- Mcp1, chemokine (C–C motif) ligand 1
- Non-alcoholic fatty liver disease
- Non-alcoholic steatohepatitis
- Pgc1, peroxisome proliferator-activated receptor coactivator 1
- SREBP1c, sterol regulatory element binding transcription factor 1c
- Scd1, stearoyl-coenzyme A desaturase
- Tnf, tumor necrosis factor
- UPD, ubiquitin (Ub)-dependent proteasomal degradation
- Ub, ubiquitin
- gp78/AMFR E3 ubiquitin ligase
- gp78/AMFR, autocrine motility factor receptor
- shRNAi, shRNA interference
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Qian Y, Yang Y, Wang K, Zhou W, Dang Y, Zhu M, Li F, Ji G. 2'-Hydroxychalcone Induced Cytotoxicity via Oxidative Stress in the Lipid-Loaded Hepg2 Cells. Front Pharmacol 2019; 10:1390. [PMID: 31824319 PMCID: PMC6880759 DOI: 10.3389/fphar.2019.01390] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 10/31/2019] [Indexed: 12/14/2022] Open
Abstract
Licorice is a common herb used in traditional Chinese medicine, and has been widely used clinically. Physiologically, although it is relatively safe, licorice-induced hepatotoxicity in the presence of other diseases needs to be evaluated. The present study was conducted to investigate the toxicological effects of the bioactive components of licorice in HepG2 cells cultured with or without free fatty acid (FFA). The compounds, isoliquiritigenin, licorice chalcone A, bavachalcone, and 2'-hydroxy chalcone (2'-HC) inhibited cell proliferation at certain concentrations in lipid loaded cells with limited effects on the normal cells. The representative compound 2'-HC (at a concentration of ≥ 20µM) increased the oxygen consumption rate, ATP production, mitochondrial membrane potential, generation of total and mitochondrial reactive oxygen species (ROS) production, and expression of inflammatory cytokines (TNF-α, IL-6, and IL-8) and Caspase-9 protein; and reduced the expression of SOD1. In addition, we found exaggerated lipid accumulation in HepG2 cells treated with FFA. Our results suggest that 2'-HC at a concentration of ≥ 20µM might cause damage to the hepatocytes. The toxicity may be related to excess ROS production and inadequate SOD1 expression, leading to apoptosis, inflammation, and cellular dysfunctions.
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Affiliation(s)
- Yun Qian
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yang Yang
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Kai Wang
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wenjun Zhou
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yanqi Dang
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Mingzhe Zhu
- School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Fenghua Li
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine, Shanghai, China
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11
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Anand L, Choudhury A, Bihari C, Sharma BC, Kumar M, Maiwall R, Siam Tan S, Shah SR, Hamid S, Butt AS, Jafri W, Chawla YK, Taneja S, Duseja A, Dhiman RK, Mahtab MA, Ghazinyan H, Duan Z, Chen Y, Shukla A, Hu J, Abbas Z, Treeprasertsuk S, Lesmana LA, Lesmana CR, Sollano JD, Carpio G, Sahu MK, Kumar G, Sarin SK. Flare of Autoimmune Hepatitis Causing Acute on Chronic Liver Failure: Diagnosis and Response to Corticosteroid Therapy. Hepatology 2019; 70:587-596. [PMID: 30113706 DOI: 10.1002/hep.30205] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2018] [Accepted: 06/25/2018] [Indexed: 01/14/2023]
Abstract
Autoimmune hepatitis (AIH) is considered less common in the Asia Pacific region. Due to this, AIH flare as a cause of acute on chronic liver failure (ACLF) is often overlooked and treatment delayed. We aimed at the defining clinical and histopathological spectrum and role of steroid therapy in AIH-ACLF. Patients with AIH-ACLF, prospectively recruited and followed between 2012 and 2017, were analyzed from the Asian Pacific Association for the Study of the Liver ACLF Research Consortium (AARC) data base. Diagnosis of AIH was confirmed using International Autoimmune Hepatitis Group score or simplified AIH score with histopathological evidence. Of 2,825 ACLF patients, 82 (2.9%) fulfilled criteria of AIH (age 42.1 ± 18.1 years, 70% female). At baseline, mean bilirubin was 18.6 ± 8.2 mg/dL, Child-Turcotte-Pugh score was 11.7 ± 1.4, and Model for End-Stage Liver Disease (MELD) score was 27.6 ± 6.5. Mean immunoglobulin G was 21.61 ± 7.32 g/dL, and this was elevated ≥1.1 times in 97% of cases; 49% were seronegative. Liver histology was available in 90%, with median histological activity index of 10 (interquartile range, 7-12); 90% with moderate to severe interface activity; 56% showing significant parenchymal necrosis (bridging and confluent necrosis); and cirrhosis in 42%. Twenty-eight (34%) patients received steroid therapy and showed shorter intensive care unit (ICU) stay (median 1.5 versus 4 days, P < 0.001) and improved 90-day survival (75% versus 48.1%, P = 0.02) with comparable incidence of sepsis (P = 0.32) compared to those who did not. Patients of advanced age, more severe liver disease (MELD >27; 83.3% sensitivity, 78.9% specificity, area under the receiver operating characteristic curve 0.86), presence of hepatic encephalopathy, and fibrosis grade ≥F3 had an unfavorable response to corticosteroid therapy. Conclusion: AIH presenting as ACLF is not uncommon in Asian patients; a low threshold for liver biopsy is needed to confirm the diagnosis as nearly half the patients are seronegative; early stratification to steroid therapy or liver transplantation (MELD >27, hepatic encephalopathy in ≥F3) would reduce ICU stay and improve outcomes.
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Affiliation(s)
- Lovkesh Anand
- Institute of Liver and Biliary Sciences, New Delhi, India
| | | | - Chhagan Bihari
- Institute of Liver and Biliary Sciences, New Delhi, India
| | | | - Manoj Kumar
- Institute of Liver and Biliary Sciences, New Delhi, India
| | - Rakhi Maiwall
- Institute of Liver and Biliary Sciences, New Delhi, India
| | | | | | - Saeed Hamid
- Medicine, Aga Khan University, Karachi, Pakistan
| | - Amna S Butt
- Medicine, Aga Khan University, Karachi, Pakistan
| | - Wasim Jafri
- Medicine, Aga Khan University, Karachi, Pakistan
| | | | | | | | | | - Mamun Al Mahtab
- Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | | | - Zhongping Duan
- Hepatology, Youan Hospital, Capital Medical University, Beijing, China
| | | | | | | | | | | | | | | | | | - Gian Carpio
- University of Santos Tomas, Manila, Philippines
| | | | - Guresh Kumar
- Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shiv K Sarin
- Institute of Liver and Biliary Sciences, New Delhi, India
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12
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Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D. The clinical usage and definition of autoantibodies in immune-mediated liver disease: A comprehensive overview. J Autoimmun 2018; 95:144-158. [DOI: 10.1016/j.jaut.2018.10.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 10/09/2018] [Accepted: 10/11/2018] [Indexed: 02/06/2023]
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13
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Sebode M, Weiler-Normann C, Liwinski T, Schramm C. Autoantibodies in Autoimmune Liver Disease-Clinical and Diagnostic Relevance. Front Immunol 2018; 9:609. [PMID: 29636752 PMCID: PMC5880919 DOI: 10.3389/fimmu.2018.00609] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 03/12/2018] [Indexed: 12/12/2022] Open
Abstract
Testing for liver-related autoantibodies should be included in the workup of patients with hepatitis or cholestasis of unknown origin. Although most of these autoantibodies are not disease specific, their determination is a prerequisite to diagnose autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC), and they are components of the diagnostic scoring system in these diseases. In primary sclerosing cholangitis (PSC), on the other hand, autoantibodies are frequently present but play a minor role in establishing the diagnosis. In PSC, however, data on antibodies suggest a link between disease pathogenesis and the intestinal microbiota. This review will focus on practical aspects of antibody testing in the three major autoimmune liver diseases AIH, PBC, and PSC.
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Affiliation(s)
- Marcial Sebode
- 1st Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Christina Weiler-Normann
- 1st Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Timur Liwinski
- 1st Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Schramm
- 1st Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
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14
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Dang NL, Hughes TB, Miller GP, Swamidass SJ. Computational Approach to Structural Alerts: Furans, Phenols, Nitroaromatics, and Thiophenes. Chem Res Toxicol 2017; 30:1046-1059. [PMID: 28256829 DOI: 10.1021/acs.chemrestox.6b00336] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Structural alerts are commonly used in drug discovery to identify molecules likely to form reactive metabolites and thereby become toxic. Unfortunately, as useful as structural alerts are, they do not effectively model if, when, and why metabolism renders safe molecules toxic. Toxicity due to a specific structural alert is highly conditional, depending on the metabolism of the alert, the reactivity of its metabolites, dosage, and competing detoxification pathways. A systems approach, which explicitly models these pathways, could more effectively assess the toxicity risk of drug candidates. In this study, we demonstrated that mathematical models of P450 metabolism can predict the context-specific probability that a structural alert will be bioactivated in a given molecule. This study focuses on the furan, phenol, nitroaromatic, and thiophene alerts. Each of these structural alerts can produce reactive metabolites through certain metabolic pathways but not always. We tested whether our metabolism modeling approach, XenoSite, can predict when a given molecule's alerts will be bioactivated. Specifically, we used models of epoxidation, quinone formation, reduction, and sulfur-oxidation to predict the bioactivation of furan-, phenol-, nitroaromatic-, and thiophene-containing drugs. Our models separated bioactivated and not-bioactivated furan-, phenol-, nitroaromatic-, and thiophene-containing drugs with AUC performances of 100%, 73%, 93%, and 88%, respectively. Metabolism models accurately predict whether alerts are bioactivated and thus serve as a practical approach to improve the interpretability and usefulness of structural alerts. We expect that this same computational approach can be extended to most other structural alerts and later integrated into toxicity risk models. This advance is one necessary step toward our long-term goal of building comprehensive metabolic models of bioactivation and detoxification to guide assessment and design of new therapeutic molecules.
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Affiliation(s)
- Na Le Dang
- Department of Pathology and Immunology, Washington University School of Medicine , Campus Box 8118, 660 S. Euclid Avenue, St. Louis, Missouri 63110, United States
| | - Tyler B Hughes
- Department of Pathology and Immunology, Washington University School of Medicine , Campus Box 8118, 660 S. Euclid Avenue, St. Louis, Missouri 63110, United States
| | - Grover P Miller
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences , Little Rock, Arkansas 72205, United States
| | - S Joshua Swamidass
- Department of Pathology and Immunology, Washington University School of Medicine , Campus Box 8118, 660 S. Euclid Avenue, St. Louis, Missouri 63110, United States
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15
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Mitra S, Minz RW. Autoantibodies in Autoimmune Liver Diseases-Methods of Detection and Interpretation: An Update for the Reporting Pathologist. Int J Surg Pathol 2016; 24:576-85. [PMID: 27388199 DOI: 10.1177/1066896916657643] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Autoimmune liver disease (AILD) is a type of chronic liver disease with autoimmune etiology. The diagnosis of the disease is multipronged and detection of autoantibodies in AILDs is an important diagnostic tool and it also helps in the classification of the disease. There are multiple autoantibodies that are detected in AILDs but none is diagnostic. Moreover, these autoantibodies are detected in many other pathological and nonpathological conditions. So the significance of seropositivity for these autoantibodies should be known by both the pathologists as well as the clinicians. In addition, there is prognostic significance associated with some of the antibodies and they also sometimes help in the disease monitoring. The whole array of antibodies detected in AILDs is discussed in detail in this review along with their clinical significance and interpretation.
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Affiliation(s)
- Suvradeep Mitra
- PGIMER (Post-Graduate Institute of Medical Education and Research), Chandigarh, India
| | - Ranjana Walker Minz
- PGIMER (Post-Graduate Institute of Medical Education and Research), Chandigarh, India
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16
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Rana P, Will Y, Nadanaciva S, Jones LH. Development of a cell viability assay to assess drug metabolite structure-toxicity relationships. Bioorg Med Chem Lett 2016; 26:4003-6. [PMID: 27397500 DOI: 10.1016/j.bmcl.2016.06.088] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2016] [Revised: 06/28/2016] [Accepted: 06/29/2016] [Indexed: 01/24/2023]
Abstract
Many adverse drug reactions are caused by the cytochrome P450 (CYP)-dependent activation of drugs into reactive metabolites. In order to reduce attrition due to metabolism-induced toxicity and to improve the safety of drug candidates, we developed a simple cell viability assay by combining a bioactivation system (human CYP3A4, CYP2D6 and CYP2C9) with Hep3B cells. We screened a series of drugs to explore structural motifs that may be responsible for CYP450-dependent activation caused by reactive metabolite formation, which highlighted specific liabilities regarding certain phenols and anilines.
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Affiliation(s)
- Payal Rana
- Drug Safety Research & Development, Pfizer, Eastern Point Road, Groton, CT 06340, USA
| | - Yvonne Will
- Drug Safety Research & Development, Pfizer, Eastern Point Road, Groton, CT 06340, USA
| | - Sashi Nadanaciva
- Compound Safety Prediction, Pfizer, Eastern Point Road, Groton, CT 06340, USA
| | - Lyn H Jones
- Medicine Design, Pfizer, 610 Main St., Cambridge, MA 02139, USA.
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17
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Kim SM, Wang Y, Nabavi N, Liu Y, Correia MA. Hepatic cytochromes P450: structural degrons and barcodes, posttranslational modifications and cellular adapters in the ERAD-endgame. Drug Metab Rev 2016; 48:405-33. [PMID: 27320797 DOI: 10.1080/03602532.2016.1195403] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The endoplasmic reticulum (ER)-anchored hepatic cytochromes P450 (P450s) are enzymes that metabolize endo- and xenobiotics i.e. drugs, carcinogens, toxins, natural and chemical products. These agents modulate liver P450 content through increased synthesis or reduction via inactivation and/or proteolytic degradation, resulting in clinically significant drug-drug interactions. P450 proteolytic degradation occurs via ER-associated degradation (ERAD) involving either of two distinct routes: Ubiquitin (Ub)-dependent 26S proteasomal degradation (ERAD/UPD) or autophagic lysosomal degradation (ERAD/ALD). CYP3A4, the major human liver/intestinal P450, and the fast-turnover CYP2E1 species are degraded via ERAD/UPD entailing multisite protein phosphorylation and subsequent ubiquitination by gp78 and CHIP E3 Ub-ligases. We are gaining insight into the nature of the structural determinants involved in CYP3A4 and CYP2E1 molecular recognition in ERAD/UPD [i.e. K48-linked polyUb chains and linear and/or "conformational" phosphodegrons consisting either of consecutive sequences on surface loops and/or disordered regions, or structurally-assembled surface clusters of negatively charged acidic (Asp/Glu) and phosphorylated (Ser/Thr) residues, within or vicinal to which, Lys-residues are targeted for ubiquitination]. Structural inspection of select human liver P450s reveals that such linear or conformational phosphodegrons may indeed be a common P450-ERAD/UPD feature. By contrast, although many P450s such as the slow-turnover CYP2E1 species and rat liver CYP2B1 and CYP2C11 are degraded via ERAD/ALD, little is known about the mechanism of their ALD-targeting. On the basis of our current knowledge of ALD-substrate targeting, we propose a tripartite conjunction of K63-linked Ub-chains, P450 structural "LIR" motifs and selective cellular "cargo receptors" as plausible P450-ALD determinants.
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Affiliation(s)
- Sung-Mi Kim
- a Department of Cellular & Molecular Pharmacology , University of California San Francisco , San Francisco , CA , USA
| | - YongQiang Wang
- a Department of Cellular & Molecular Pharmacology , University of California San Francisco , San Francisco , CA , USA
| | - Noushin Nabavi
- a Department of Cellular & Molecular Pharmacology , University of California San Francisco , San Francisco , CA , USA
| | - Yi Liu
- a Department of Cellular & Molecular Pharmacology , University of California San Francisco , San Francisco , CA , USA
| | - Maria Almira Correia
- a Department of Cellular & Molecular Pharmacology , University of California San Francisco , San Francisco , CA , USA ;,b Department of Pharmaceutical Chemistry , University of California San Francisco , San Francisco , CA , USA ;,c Department of Bioengineering and Therapeutic Sciences , University of California San Francisco , San Francisco , CA , USA ;,d The Liver Center, University of California San Francisco , San Francisco , CA , USA
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18
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An analysis of drug-induced liver injury, which showed histological findings similar to autoimmune hepatitis. J Gastroenterol 2016; 51:597-607. [PMID: 26519284 DOI: 10.1007/s00535-015-1131-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2014] [Accepted: 10/03/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND Drug-induced liver injury (DILI) sometimes resembles autoimmune hepatitis (AIH) in its hepatic histology. However, there is lacking data of a comparison of the characteristics between such DILI and DILI without histological findings like AIH. METHODS We enrolled 62 patients with DILI who were diagnosed using the Roussel Uclaf Causality Assessment Method, and performed a liver biopsy. These patients were classified into two groups: DILI with histology like AIH (group A, n = 23) and DILI without such histology (group B, n = 39). Sixteen patients of group A could be further classified into two groups: patients with relapse of the liver injury (group C, n = 8) and without relapse (group D, n = 8), after the recovery of the DILI. We compared the clinical and histological findings between group A and B, and group C versus D. RESULTS Group A was characterized by an older age (p = 0.043), higher immunoglobulin G level (p = 0.017), positive antinuclear antibody status (p = 0.044), and a higher frequency of complementary alternative medicines and Chinese herbal medicines as the causative drug (p = 0.008). There were no significant differences between group C and D regarding the clinical data and liver histological findings. CONCLUSIONS The clinical characteristics of DILI, which showed histological findings similar to AIH, were revealed. In such patients, a liver biopsy is recommended in order to determine the appropriate treatment strategy. In DILI with histology like AIH patients, long-term follow-up is needed to perceive the relapse.
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19
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Abstract
Drug-induced liver injury (DILI) is among the most challenging acute or chronic liver conditions to be handled by physicians. Despite its low incidence in the general population, DILI is a frequent cause of acute liver failure. As such, the possibility of DILI should be considered in all patients who present with acute liver damage, independent of any known pre-existing liver disease. DILI can be classified as intrinsic/dose-dependent (e.g., acetaminophen toxicity) or idiosyncratic/dose-independent, with the latter form being relatively uncommon. Amoxicillin-clavulanate is the antimicrobial that is most frequently associated with idiosyncratic DILI. Large, ongoing, prospective studies in western countries have reported other drugs associated with DILI, including nonsteroidal anti-inflammatory drugs, statins, and herbal and dietary supplements. An important safety issue, DILI is one of the most frequently cited reasons for cessation of drug development during or after preclinical studies and for withdrawal of a drug from the market. This review summarizes the epidemiology, risk factors, commonly implicated drugs, clinical features, and diagnosis of DILI, with the aim of aiding physicians in the management of this debated problem. Old and new biomarkers for DILI and pharmacogenetic studies are also described.
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Affiliation(s)
- Anna Licata
- Sezione di Gastroenterologia & Epatologia, Dipartimento di Medicina Interna e Specialistica, DiBiMIS, Università di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy.
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20
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Moole H, Ahmed Z, Saxena N, Puli SR, Dhillon S. Oral clindamycin causing acute cholestatic hepatitis without ductopenia: a brief review of idiosyncratic drug-induced liver injury and a case report. J Community Hosp Intern Med Perspect 2015; 5:28746. [PMID: 26486111 PMCID: PMC4612703 DOI: 10.3402/jchimp.v5.28746] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Revised: 07/25/2015] [Accepted: 08/03/2015] [Indexed: 01/20/2023] Open
Abstract
Clindamycin is a lincosamide antibiotic active against most of the anaerobes, protozoans, and Gram-positive bacteria, including community-acquired methicillin-resistant Staphylococcus aureus. Its use has increased greatly in the recent past due to wide spectrum of activity and good bioavailability in oral form. Close to 20% of the patients taking clindamycin experience diarrhea as the most common side effect. Hepatotoxicity is a rare side effect. Systemic clindamycin therapy has been linked to two forms of hepatotoxicity: transient serum aminotransferase elevation and an acute idiosyncratic liver injury that occurs 1–3 weeks after starting therapy. This article is a case report of oral clindamycin induced acute symptomatic cholestatic hepatitis and a brief review of the topic.
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Affiliation(s)
- Harsha Moole
- Division of General Internal Medicine, University of Illinois College of Medicine at Peoria, Peoria, IL, USA;
| | - Zohair Ahmed
- Division of General Internal Medicine, University of Illinois College of Medicine at Peoria, Peoria, IL, USA
| | - Nibha Saxena
- Division of Pathology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA
| | - Srinivas R Puli
- Division of Gastroenterology and Hepatology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA
| | - Sonu Dhillon
- Division of Gastroenterology and Hepatology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA
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21
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Affiliation(s)
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- EASL office, 7 Rue Daubin, CH 1203 Geneva, Switzerland,
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22
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Teo YL, Ho HK, Chan A. Formation of reactive metabolites and management of tyrosine kinase inhibitor-induced hepatotoxicity: a literature review. Expert Opin Drug Metab Toxicol 2015; 11:231-242. [PMID: 25400226 DOI: 10.1517/17425255.2015.983075] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Existing clinical evidence indicates that many tyrosine kinase inhibitors (TKIs) are associated with idiosyncratic hepatotoxicity. TKIs possess risk factors for developing drug-induced liver injury such as their high daily dose, being substrates of P450 enzyme and being involved in significant hepatic metabolism. Several successful strategies to overcome TKI-induced hepatotoxicity include: switching to an alternative TKI with a similar mechanism of action, using an alternative dose and introduction of corticosteroids for treatment and prevention of hepatotoxicity. AREAS COVERED This review highlights the formation of reactive metabolites and how this leads to toxicity, as well as the current clinical management of TKI-induced hepatotoxicity. EXPERT OPINION Numerous events need to occur in an individual patient before converging into an idiosyncratic hepatotoxicity episode. Of these, the formation of a reactive intermediate through metabolism appears to be the prerequisite. This critical event involves an intricate chemico-biological interaction where, on one hand, drug-specific characteristics create the propensity for occurrence and, on the other hand, patient risk factors determine the individuality of response. With improved understanding of the mechanisms leading to adverse events, several strategies are being adopted to prevent and treat TKI-induced hepatotoxicity. However, further evidence is required before they can be recommended to larger populations.
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Affiliation(s)
- Yi Ling Teo
- National University of Singapore, Department of Pharmacy, Faculty of Science , 18 Science Drive 4, Singapore 117543 , Singapore +65 6516 7814, +65 6516 7963 ; +65 6779 1554 ; ,
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23
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Abstract
Mechanism-based inactivation (MBI) of CYP450 enzymes is a unique form of inhibition in which the enzymatic machinery of the victim is responsible for generation of the reactive metabolite. This precondition sets up a time-dependency for the inactivation process, a hallmark feature that characterizes all MBI. Yet, MBI itself is a complex biochemical phenomenon that operates in different modes, namely, covalent binding to apoprotein, covalent binding of the porphyrin group and also complexation of the catalytic iron. Using lapatinib as a recent example of toxicological interest, we present an example of a mixed-function MBI that can confound clinical drug-drug interactions manifestation. Lapatinib exhibits both covalent binding to the apoprotein and formation of a metabolite-intermediate complex in an enzyme-selective manner (CYP3A4 versus CYP3A5), each with different reactive metabolites. The clinical implication of this effect is also contingent upon genetic polymorphisms of the enzyme involved as well as the co-administration of other substrates, inhibitors or inducers, culminating in drug-drug interactions. This understanding recapitulates the importance of applying isoform-specific mechanistic investigations to develop customized strategies to manage such outcomes.
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Affiliation(s)
- Han Kiat Ho
- Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, 117543, Singapore
| | - Chun Yip Chan
- Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, 117543, Singapore
| | - Klarissa D Hardy
- College of Pharmacy, Lipscomb University, 1 University Park Drive, Nashville, TN 37204-3951, USA
| | - Eric Chun Yong Chan
- Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, 117543, Singapore
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Gramec D, Peterlin Mašič L, Sollner Dolenc M. Bioactivation potential of thiophene-containing drugs. Chem Res Toxicol 2014; 27:1344-58. [PMID: 25014778 DOI: 10.1021/tx500134g] [Citation(s) in RCA: 178] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Thiophene is a five-membered, sulfur-containing heteroaromatic ring commonly used as a building block in drugs. It is considered to be a structural alert, as its metabolism can lead to the formation of reactive metabolites. Thiophene S-oxides and thiophene epoxides are highly reactive electrophilic thiophene metabolites whose formation is cytochrome P450-dependent. These reactive thiophene-based metabolites are quite often responsible for drug-induced hepatotoxicity. Tienilic acid is an example of a thiophene-based drug that was withdrawn from the market after only a few months of use, due to severe cases of immune hepatitis. However, inclusion of the thiophene moiety in drugs does not necessarily result in toxic effects. The presence of other, less toxic metabolic pathways, as well as an effective detoxification system in our body, protects us from the bioactivation potential of the thiophene ring. Thus, the presence of a structural alert itself is insufficient to predict a compound's toxicity. The question therefore arises as to which factors significantly influence the toxicity of thiophene-containing drugs. There is no easy way to answer this question. However, the findings presented here indicate that, for a number of reasons, daily dose and alternative metabolic pathways are important factors when predicting toxicity and will therefore be discussed together with examples.
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Affiliation(s)
- Darja Gramec
- Faculty of Pharmacy, University of Ljubljana , Aškerčeva 7, 1000 Ljubljana, Slovenia
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25
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Tak S, Tak S. Acute hepatitis after starting pinaverium bromide in a patient taking mirtazapine. BMJ Case Rep 2014; 2014:bcr-2013-200947. [PMID: 25015163 DOI: 10.1136/bcr-2013-200947] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
A 56-year-old man presented with chronic abdominal pain. He had been evaluated extensively in the recent past undergoing upper gastrointestinal endoscopy, colonoscopy and CT scan of the abdomen with normal results. The provisional diagnosis of irritable bowel syndrome was performed and pinaverium bromide was started. The patient had pre-existing hypertension, a major depressive disorder and gastro-oesophageal reflux disease. He had been taking nebivolol and pantoprazole for several years and mirtazapine for the last 1 year. The patient developed nausea, vomiting and anorexia after 5 days of starting pinaverium bromide. Investigations revealed marked elevation of liver enzymes and bilirubin. He was negative for HIV, HBSAg, anti-hepatitis C virus, IgM for hepatitis A virus, hepatitis E virus, antinuclear antibody and antimitochondrial antibody. An ultrasound showed mild hepatomegaly with hypoechoic echo texture; the rest of scan was normal. Pinaverium and mirtazapine were stopped immediately. The patient was treated symptomatically and his liver profile returned to normal after 4 weeks.
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Affiliation(s)
- Sandeep Tak
- Department of Medicine, SN Medical College, Jodhpur, Rajasthan, India
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26
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Liberal R, Grant CR, Longhi MS, Mieli-Vergani G, Vergani D. Diagnostic criteria of autoimmune hepatitis. Autoimmun Rev 2014; 13:435-40. [PMID: 24418295 DOI: 10.1016/j.autrev.2013.11.009] [Citation(s) in RCA: 83] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/13/2013] [Indexed: 12/16/2022]
Abstract
Autoimmune hepatitis (AIH) is a chronic immune-mediated liver disorder characterised by female preponderance, elevated transaminase and immunoglobulin G levels, seropositivity for autoantibodies and interface hepatitis. Presentation is highly variable, therefore AIH should be considered during the diagnostic workup of any increase in liver enzyme levels. A set of inclusion and exclusion criteria for the diagnosis of AIH have been established by the International Autoimmune Hepatitis Group (IAIHG). There are two main types of AIH: type 1, positive for anti-nuclear (ANA) and/or anti-smooth muscle antibodies (SMAs) and type 2, defined by the presence of anti-liver kidney microsomal antibody type 1 (LKM-1) and/or anti-liver cytosol type 1 (LC-1) autoantibodies. The central role of autoantibodies in the diagnosis of AIH has led the IAIHG to produce a consensus statement detailing appropriate and effective methods for their detection. Autoantibodies should be tested by indirect immunofluorescence at an initial dilution of 1/40 in adults and 1/10 in children on a freshly prepared rodent substrate that includes kidney, liver and stomach sections to allow for the simultaneous detection of all reactivities relevant to AIH. Anti-LKM-1 is often confused with anti-mitochondrial antibody (AMA) if rodent kidney is used as the sole immunofluorescence substrate. The identification of the molecular targets of anti-LKM-1 and AMA has led to the establishment of immuno-assays based on the use of the recombinant or purified autoantigens. Perinuclear anti-nuclear neutrophil antibody (p-ANNA) is an additional marker of AIH-1; anti soluble liver antigen (SLA) antibodies are specific for autoimmune liver disease, can be present in AIH-1 and AIH-2 and are associated with a more severe clinical course. Anti-SLA are detectable by ELISA or radio-immuno-assays, but not by immunofluorescence. AIH is exquisitely responsive to immunosuppressive treatment, which should be instituted promptly to prevent rapid deterioration and promote remission and long-term survival.
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Affiliation(s)
- Rodrigo Liberal
- Paediatric Liver, GI & Nutrition Centre and Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, UK; Faculty of Medicine, University of Porto, Porto, Portugal
| | - Charlotte R Grant
- Paediatric Liver, GI & Nutrition Centre and Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, UK
| | - Maria Serena Longhi
- Paediatric Liver, GI & Nutrition Centre and Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, UK
| | - Giorgina Mieli-Vergani
- Paediatric Liver, GI & Nutrition Centre and Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, UK
| | - Diego Vergani
- Paediatric Liver, GI & Nutrition Centre and Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, UK.
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Zahno A, Bouitbir J, Maseneni S, Lindinger PW, Brecht K, Krähenbühl S. Hepatocellular toxicity of clopidogrel: mechanisms and risk factors. Free Radic Biol Med 2013; 65:208-216. [PMID: 23770199 DOI: 10.1016/j.freeradbiomed.2013.06.007] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2012] [Revised: 05/11/2013] [Accepted: 06/04/2013] [Indexed: 12/11/2022]
Abstract
Clopidogrel is a prodrug used widely as a platelet aggregation inhibitor. After intestinal absorption, approximately 90% is converted to inactive clopidogrel carboxylate and 10% via a two-step procedure to the active metabolite containing a mercapto group. Hepatotoxicity is a rare but potentially serious adverse reaction associated with clopidogrel. The aim of this study was to find out the mechanisms and susceptibility factors for clopidogrel-associated hepatotoxicity. In primary human hepatocytes, clopidogrel (10 and 100 μM) was cytotoxic only after cytochrome P450 (CYP) induction by rifampicin. Clopidogrel (10 and 100 μM) was also toxic for HepG2 cells expressing human CYP3A4 (HepG2/CYP3A4) and HepG2 cells co-incubated with CYP3A4 supersomes (HepG2/CYP3A4 supersome), but not for wild-type HepG2 cells (HepG2/wt). Clopidogrel (100 μM) decreased the cellular glutathione content in HepG2/CYP3A4 supersome and triggered an oxidative stress reaction (10 and 100 µM) in HepG2/CYP3A4, but not in HepG2/wt. Glutathione depletion significantly increased the cytotoxicity of clopidogrel (10 and 100 µM) in HepG2/CYP3A4 supersome. Co-incubation with 1 μM ketoconazole or 10mM glutathione almost completely prevented the cytotoxic effect of clopidogrel in HepG2/CYP3A4 and HepG2/CYP3A4 supersome. HepG2/CYP3A4 incubated with 100 μM clopidogrel showed mitochondrial damage and cytochrome c release, eventually promoting apoptosis and/or necrosis. In contrast to clopidogrel, clopidogrel carboxylate was not toxic for HepG2/wt or HepG2/CYP3A4 up to 100 µM. In conclusion, clopidogrel incubated with CYP3A4 is associated with the formation of metabolites that are toxic for hepatocytes and can be trapped by glutathione. High CYP3A4 activity and low cellular glutathione stores may be risk factors for clopidogrel-associated hepatocellular toxicity.
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Affiliation(s)
- Anja Zahno
- Division of Clinical Pharmacology & Toxicology and Department of Biomedicine, University Hospital, CH-4031 Basel, Switzerland
| | - Jamal Bouitbir
- Division of Clinical Pharmacology & Toxicology and Department of Biomedicine, University Hospital, CH-4031 Basel, Switzerland
| | - Swarna Maseneni
- Division of Clinical Pharmacology & Toxicology and Department of Biomedicine, University Hospital, CH-4031 Basel, Switzerland
| | - Peter W Lindinger
- Division of Clinical Pharmacology & Toxicology and Department of Biomedicine, University Hospital, CH-4031 Basel, Switzerland
| | - Karin Brecht
- Division of Clinical Pharmacology & Toxicology and Department of Biomedicine, University Hospital, CH-4031 Basel, Switzerland
| | - Stephan Krähenbühl
- Division of Clinical Pharmacology & Toxicology and Department of Biomedicine, University Hospital, CH-4031 Basel, Switzerland.
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28
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Mansuy D. [Metabolism of xenobiotics: beneficial and adverse effects]. Biol Aujourdhui 2013; 207:33-37. [PMID: 23694723 DOI: 10.1051/jbio/2013003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2013] [Indexed: 06/02/2023]
Abstract
The systems developed by living organisms for the metabolism of xenobiotics play a key role in the adaptation of living species to their chemical environment. Recent data about mammalian cytochrome P450 structures have led to a better understanding of the molecular basis for the adaptability of these enzymes to xenobiotics exhibiting highly variable structures. The action of these enzymes on xenobiotics leads to other beneficial effects such as the bioactivation of some drugs, but also to adverse effects with the formation of aggressive metabolites for the cell that are responsible for the appearance of many toxicities.
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Affiliation(s)
- Daniel Mansuy
- Université Paris Descartes, PRES Sorbonne Paris Cité, UMR 8601, 45 rue des Saints-Pères, 75270 Paris Cedex 06, France.
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Koen YM, Sarma D, Williams TD, Galeva NA, Obach RS, Hanzlik RP. Identification of protein targets of reactive metabolites of tienilic acid in human hepatocytes. Chem Res Toxicol 2012; 25:1145-54. [PMID: 22462724 DOI: 10.1021/tx300103j] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Tienilic acid (TA) is a uricosuric diuretic that was withdrawn from the market only months after its introduction because of reports of serious incidents of drug-induced liver injury including some fatalities. Its hepatotoxicity is considered to be primarily immunoallergic in nature. Like other thiophene compounds, TA undergoes biotransformation to a S-oxide metabolite which then reacts covalently with cellular proteins. To identify protein targets of TA metabolites, we incubated [(14)C]-TA with human hepatocytes, separated cellular proteins by 2D gel electrophoresis, and analyzed proteins in 36 radioactive spots by tryptic digestion followed by LC-MS/MS. Thirty-one spots contained at least one identifiable protein. Sixteen spots contained only one of 14 nonredundant proteins which were thus considered to be targets of TA metabolites. Six of the 14 were also found in other radioactive spots that contained from 1 to 3 additional proteins. Eight of the 14 had not been reported to be targets for any reactive metabolite other than TA. The other 15 spots each contained from 2 to 4 identifiable proteins, many of which are known targets of other chemically reactive metabolites, but since adducted peptides were not observed, the identity of the adducted protein(s) in these spots is ambiguous. Interestingly, all the radioactive spots corresponded to proteins of low abundance, while many highly abundant proteins in the mixture showed no radioactivity. Furthermore, of approximately 16 previously reported protein targets of TA in rat liver ( Methogo, R., Dansette, P., and Klarskov, K. ( 2007 ) Int. J. Mass Spectrom. , 268 , 284 -295 ), only one (fumarylacetoacetase) is among the 14 targets identified in this work. One reason for this difference may be statistical, given that each study identified a small number of targets from among thousands present in hepatocytes. Another may be the species difference (i.e., rat vs human), and still another may be the method of detection of adducted proteins (i.e., Western blot vs C-14). Knowledge of human target proteins is very limited. Of more than 350 known protein targets of reactive metabolites, only 42 are known from humans, and only 21 of these are known to be targets for more than one chemical. Nevertheless, the demonstration that human target proteins can be identified using isolated hepatocytes in vitro should enable the question of species differences to be addressed more fully in the future.
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Affiliation(s)
- Yakov M Koen
- Department of Medicinal Chemistry and ‡Mass Spectrometry Laboratory, University of Kansas, Lawrence, KS 66045, United States
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Sevior DK, Pelkonen O, Ahokas JT. Hepatocytes: the powerhouse of biotransformation. Int J Biochem Cell Biol 2011; 44:257-61. [PMID: 22123318 DOI: 10.1016/j.biocel.2011.11.011] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2010] [Revised: 10/12/2011] [Accepted: 11/14/2011] [Indexed: 01/10/2023]
Abstract
Liver is the most important organ involved in biotransformation of xenobiotics. Within the main organisational unit, the hepatocyte, is an assembly of enzymes commonly classified as phase I and phase II enzymes. The phase I enzymes principally cytochrome P450 catalyse both oxidative and reductive reactions of a bewildering number of xenobiotics. Many of the products of phase I enzymes become substrates for the phase II enzymes, which catalyse conjugation reactions making use of endogenous cofactors. As xenobiotic metabolising enzymes are responsible for the toxicity of many chemicals and drugs, testing the role of the biotransformation enzymes and the transporters within the hepatocyte is critical. New methodologies may be able to provide information to allow for better in vitro to in vivo extrapolation of data.
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Pessayre D, Fromenty B, Berson A, Robin MA, Lettéron P, Moreau R, Mansouri A. Central role of mitochondria in drug-induced liver injury. Drug Metab Rev 2011; 44:34-87. [PMID: 21892896 DOI: 10.3109/03602532.2011.604086] [Citation(s) in RCA: 193] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
A frequent mechanism for drug-induced liver injury (DILI) is the formation of reactive metabolites that trigger hepatitis through direct toxicity or immune reactions. Both events cause mitochondrial membrane disruption. Genetic or acquired factors predispose to metabolite-mediated hepatitis by increasing the formation of the reactive metabolite, decreasing its detoxification, or by the presence of critical human leukocyte antigen molecule(s). In other instances, the parent drug itself triggers mitochondrial membrane disruption or inhibits mitochondrial function through different mechanisms. Drugs can sequester coenzyme A or can inhibit mitochondrial β-oxidation enzymes, the transfer of electrons along the respiratory chain, or adenosine triphosphate (ATP) synthase. Drugs can also destroy mitochondrial DNA, inhibit its replication, decrease mitochondrial transcripts, or hamper mitochondrial protein synthesis. Quite often, a single drug has many different effects on mitochondrial function. A severe impairment of oxidative phosphorylation decreases hepatic ATP, leading to cell dysfunction or necrosis; it can also secondarily inhibit ß-oxidation, thus causing steatosis, and can also inhibit pyruvate catabolism, leading to lactic acidosis. A severe impairment of β-oxidation can cause a fatty liver; further, decreased gluconeogenesis and increased utilization of glucose to compensate for the inability to oxidize fatty acids, together with the mitochondrial toxicity of accumulated free fatty acids and lipid peroxidation products, may impair energy production, possibly leading to coma and death. Susceptibility to parent drug-mediated mitochondrial dysfunction can be increased by factors impairing the removal of the toxic parent compound or by the presence of other medical condition(s) impairing mitochondrial function. New drug molecules should be screened for possible mitochondrial effects.
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Affiliation(s)
- Dominique Pessayre
- INSERM, U, Centre de Recherche Bichat Beaujon CRB, Faculté de Médecine Xavier-Bichat, Paris, France.
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Hosomi H, Fukami T, Iwamura A, Nakajima M, Yokoi T. Development of a highly sensitive cytotoxicity assay system for CYP3A4-mediated metabolic activation. Drug Metab Dispos 2011; 39:1388-95. [PMID: 21540358 DOI: 10.1124/dmd.110.037077] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/13/2025] Open
Abstract
Drug-induced hepatotoxicity, which is a rare but serious adverse reaction to a large number of pharmaceutical drugs, is sometimes associated with reactive metabolites produced by drug-metabolizing enzymes. In the present study, we constructed a cell-based system to evaluate the cytotoxicity of reactive metabolites produced by CYP3A4 using human hepatoma cells infected with an adenovirus vector expressing human CYP3A4 (AdCYP3A4). When seven hepatoma cell lines (HepG2, Hep3B, HLE, HLF, Huh6, Huh7, and Fa2N4 cells) were infected with AdCYP3A4, HepG2 cells showed the highest CYP3A4 protein expression and testosterone 6β-hydroxylase activity (670 pmol · min(-1) · mg(-1)). With the use of AdCYP3A4-infected HepG2 cells, the cytotoxicities of 23 drugs were evaluated by the 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium monosodium salt assay, and the cell viability when treated with 11 drugs (amiodarone, desipramine, felbamate, isoniazid, labetalol, leflunomide, nefazodone, nitrofurantoin, tacrine, terbinafine, and tolcapone) was significantly decreased. Moreover, the transfection of siRNA for nuclear factor erythroid 2-related factor 2 (Nrf2) to decrease the cellular expression level of Nrf2 exacerbated the cytotoxicity of some drugs (troglitazone, flutamide, acetaminophen, clozapine, terbinafine, and desipramine), suggesting that the genes regulated by Nrf2 are associated with the detoxification of the cytotoxicities mediated by CYP3A4. We constructed a highly sensitive cell-based system to detect the drug-induced cytotoxicity mediated by CYP3A4. This system would be beneficial in preclinical screening in drug development and increase our understanding of the drug-induced cytotoxicity associated with CYP3A4.
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Affiliation(s)
- Hiroko Hosomi
- Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
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Takakusa H, Wahlin MD, Zhao C, Hanson KL, New LS, Chan ECY, Nelson SD. Metabolic intermediate complex formation of human cytochrome P450 3A4 by lapatinib. Drug Metab Dispos 2011; 39:1022-30. [PMID: 21363997 PMCID: PMC3100900 DOI: 10.1124/dmd.110.037531] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2010] [Accepted: 02/28/2011] [Indexed: 01/22/2023] Open
Abstract
Lapatinib, an oral breast cancer drug, has recently been reported to be a mechanism-based inactivator of cytochrome P450 (P450) 3A4 and also an idiosyncratic hepatotoxicant. It was suggested that formation of a reactive quinoneimine metabolite was involved in mechanism-based inactivation (MBI) and/or hepatotoxicity. We investigated the mechanism of MBI of P450 3A4 by lapatinib. Liquid chromatography-mass spectrometry analysis of P450 3A4 after incubation with lapatinib did not show any peak corresponding to irreversible modifications. The enzymatic activity inactivated by lapatinib was completely restored by the addition of potassium ferricyanide. These results indicate that the mechanism of MBI by lapatinib is quasi-irreversible and mediated via metabolic intermediate complex (MI complex) formation. This finding was verified by the increase in a signature Soret absorbance at approximately 455 nm. Two amine oxidation products of the metabolism of lapatinib by P450 3A4 were characterized: N-hydroxy lapatinib (M3) and the oxime form of N-dealkylated lapatinib (M2), suggesting that a nitroso or another related intermediate generated from M3 is involved in MI complex formation. In contrast, P450 3A5 was much less susceptible to MBI by lapatinib via MI complex formation than P450 3A4. In addition, P450 3A5 had a significantly lower ability than 3A4 to generate M3, consistent with N-hydroxylation as the initial step in the pathway to MI complex formation. In conclusion, our results demonstrate that the primary mechanism for MBI of P450 3A4 by lapatinib is not irreversible modification by the quinoneimine metabolite, but quasi-irreversible MI complex formation mediated via oxidation of the secondary amine group of lapatinib.
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Affiliation(s)
- Hideo Takakusa
- Department of Medicinal Chemistry, University of Washington, Seattle, WA, USA
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35
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Abstract
The clinical phenotype of classical autoimmune hepatitis can be mimicked by idiosyncratic drug-induced liver injury, and differentiation can be difficult. The goals of this review are to enumerate the major agents of drug-induced autoimmune-like hepatitis, describe the clinical findings and risk factors associated with it, detail the clinical tools by which to assess causality, discuss putative pathogenic mechanisms, and describe treatment and outcome. The frequency of drug-induced autoimmune-like hepatitis among patients with classical features of autoimmune hepatitis is 9%. Minocycline and nitrofurantoin are implicated in 90% of cases. Female predominance, acute onset, and absence of cirrhosis at presentation are important clinical manifestations. Genetic factors affecting phase I and phase II transformations of the drug, polymorphisms that protect against cellular oxidative stress, and human leukocyte antigens that modulate the immune response may be important pathogenic components. Clinical judgment is the mainstay of diagnosis as structured diagnostic methods for drug-induced liver injury are imperfect. The covalent binding of a reactive drug metabolite to a hepatocyte surface protein (commonly a phase I or phase II enzyme), formation of a neoantigen, activation of CD8 T lymphocytes with nonselective antigen receptors, and deficient immune regulatory mechanisms are the main bases for a transient loss of self-tolerance. Discontinuation of the offending drug is the essential treatment. Spontaneous improvement usually ensues within 1 month. Corticosteroid therapy is warranted for symptomatic severe disease, and it is almost invariably effective. Relapse after corticosteroid withdrawal probably does not occur, and its absence distinguishes drug-induced disease from classical autoimmune hepatitis.
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36
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Hu Y, Yang S, Shilliday FB, Heyde BR, Mandrell KM, Robins RH, Xie J, Reding MT, Lai Y, Thompson DC. Novel metabolic bioactivation mechanism for a series of anti-inflammatory agents (2,5-diaminothiophene derivatives) mediated by cytochrome p450 enzymes. Drug Metab Dispos 2010; 38:1522-31. [PMID: 20530221 DOI: 10.1124/dmd.110.032581] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/13/2025] Open
Abstract
The thiophene moiety is considered a structural alert in molecular design in drug discovery, largely because several thiophene-containing drugs, including tienilic acid and suprofen, have been withdrawn from the market because of toxicities. Reactive thiophene intermediates, activated via sulfur oxidation or ring epoxidation, are possible culprits for these adverse side effects. In this work, the metabolic activation of an anti-inflammatory agent, 1-(3-carbamoyl-5-(2,3,5-trichlorobenzamido)thiophen-2-yl)urea), containing a 2,5-diaminothiophene structure, was studied in liver microsomes in the presence of glutathione or N-acetylcysteine as trapping agents. In addition, the glutathione conjugate was detected in bile from a bile duct-cannulated rat study. The structure of the glutathione conjugate was identified by mass spectrometry and (1)H NMR. The glutathione molecule was attached to the thiophene ring, replacing the existing proton. Metabolic phenotyping experiments, using chemical inhibitors or recombinant cytochromes P450 (P450), demonstrated that CYP3A4 was the major P450 enzyme responsible for the metabolic activation, followed by CYP1A2, 2Cs, and 2D6. A novel metabolic activation mechanism is proposed whereby the 2,5-diaminothiophene moiety undergoes oxidation to a 2,5-diimine thiophene reactive intermediate. This mechanism was used to support efforts to eliminate reactive metabolite generation via structural modification of ring substituents using structure-activity relationships. The disruption of formation of the 2,5-diimine reactive intermediate resulted in the elimination of glutathione conjugate formation both in vitro and in vivo and provided a rational approach to mitigating potential safety risks associated with this class of thiophenes in drug research and development.
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Affiliation(s)
- Yiding Hu
- Pharmacokinetics, Dynamics and Metabolism Department, Pfizer, Inc. St. Louis Laboratory, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA.
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37
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38
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Rieder MJ. Immune mediation of hypersensitivity adverse drug reactions: implications for therapy. Expert Opin Drug Saf 2010; 8:331-43. [PMID: 19505265 DOI: 10.1517/14740330902933736] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Adverse drug reactions are among the top causes of death in the developed world, and among the spectrum of adverse drug reactions, drug hypersensitivity is a principal contributor to serious adverse drug events. The pathophysiology of drug hypersensitivity remains incompletely understood, but seems to involve the initial recognition of a drug or metabolite by the immune system followed by an immune response that determines the clinical manifestations. At present, there are two competing theories for how immune recognition occurs: the Hapten Hypothesis in which drug hapten-carrier association is the key driver for immune recognition and the Pharmacological Interference Concept that postulates direct recognition of drugs by low affinity association with the T cell receptor. The Danger Hypothesis provides a potentially important addition to the Hapten Hypothesis. Therapy for drug hypersensitivity has traditionally involved excellent supportive care. Although corticosteroids and intravenous immunoglobulin have both been used as immunomodulatory therapy, there is no robust evidence supporting the efficacy of their therapy for drug hypersensitivity. Recent advances in molecular biology and genomic pharmacology offer previously unappreciated opportunities to clarify the controversies surrounding drug hypersensitivity and to better diagnose, treat and, it is hoped, prevent drug hypersensitivity in the future.
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Affiliation(s)
- Michael J Rieder
- University of Western Ontario, Children's Health Research Institute, Schulich School of Medicine & Dentistry, Ontario, Canada.
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39
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Ariyoshi N, Iga Y, Hirata K, Sato Y, Miura G, Ishii I, Nagamori S, Kitada M. Enhanced Susceptibility of HLA-mediated Ticlopidine-induced Idiosyncratic Hepatotoxicity by CYP2B6 Polymorphism in Japanese. Drug Metab Pharmacokinet 2010; 25:298-306. [DOI: 10.2133/dmpk.25.298] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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40
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Tang W, Lu AY. Metabolic bioactivation and drug-related adverse effects: current status and future directions from a pharmaceutical research perspective. Drug Metab Rev 2009; 42:225-49. [DOI: 10.3109/03602530903401658] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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41
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Beaune PH, Lecoeur S, Bourdi M, Gauffre A, Belloc C, Dansette P, Mansuy D. Anti-cytochrome P450 autoantibodies in drug-induced disease. Eur J Haematol Suppl 2009; 60:89-92. [PMID: 8987248 DOI: 10.1111/j.1600-0609.1996.tb01652.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Drugs may induce hepatitis through immune mechanisms. In this review we have used the examples of 2 drugs to elucidate the first steps leading to the triggering of such disease, namely tienilic acid (TA) and dihydralazine (DH). These drugs are transformed into reactive metabolite(s) by cytochrome P450 (2C9 for TA and 1A2 for DH) (step 1). The reactive metabolites produced are very short-lived and bind directly to the enzymes which generated them (step 2). A neoantigen is thus formed which triggers an immune response (step 3), characterized by the presence of autoantibodies in the patient's serum (step 4). The autoantibodies are directed against the cytochrome P450 which generated the metabolite(s). Although the process by which TA and DH induce-hepatitis has been elucidated, further studies are necessary to generalize this mechanism. In addition, an animal model will also be useful to fully understand the immune mechanism of this type of disease.
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Affiliation(s)
- P H Beaune
- INSERM U 75, Université René Descartes, Paris, France.
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42
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Masubuchi Y, Horie T. Toxicological Significance of Mechanism-Based Inactivation of Cytochrome P450 Enzymes by Drugs. Crit Rev Toxicol 2008; 37:389-412. [PMID: 17612953 DOI: 10.1080/10408440701215233] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cytochrome P450 (P450) enzymes oxidize xenobiotics into chemically reactive metabolites or intermediates as well as into stable metabolites. If the reactivity of the product is very high, it binds to a catalytic site or sites of the enzyme itself and inactivates it. This phenomenon is referred to as mechanism-based inactivation. Many clinically important drugs are mechanism-based inactivators that include macrolide antibiotics, calcium channel blockers, and selective serotonin uptake inhibitors, but are not always structurally and pharmacologically related. The inactivation of P450s during drug therapy results in serious drug interactions, since irreversibility of the binding allows enzyme inhibition to be prolonged after elimination of the causal drug. The inhibition of the metabolism of drugs with narrow therapeutic indexes, such as terfenadine and astemizole, leads to toxicities. On the other hand, the fate of P450s after the inactivation and the toxicological consequences remains to be elucidated, while it has been suggested that P450s modified and degraded are involved in some forms of tissue toxicity. Porphyrinogenic drugs, such as griseofulvin, cause mechanism-based heme inactivation, leading to formation of ferrochelatase-inhibitory N-alkylated protoporphyrins and resulting in porphyria. Involvement of P450-derived free heme in halothane-induced hepatotoxicity and catalytic iron in cisplatin-induced nephrotoxicity has also been suggested. Autoantibodies against P450s have been found in hepatitis following administration of tienilic acid and dihydralazine. Tienilic acid is activated by and covalently bound to CYP2C9, and the neoantigens thus formed activate immune systems, resulting in the formation of an autoantibodydirected against CYP2C9, named anti-liver/kidney microsomal autoantibody type 2, whereas the pathological role of the autoantibodies in drug-induced hepatitis remains largely unknown.
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Affiliation(s)
- Yasuhiro Masubuchi
- Laboratory of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Chiba Institute of Science, Chosi, Japan
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43
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Obach RS, Kalgutkar AS, Soglia JR, Zhao SX. Can in vitro metabolism-dependent covalent binding data in liver microsomes distinguish hepatotoxic from nonhepatotoxic drugs? An analysis of 18 drugs with consideration of intrinsic clearance and daily dose. Chem Res Toxicol 2008; 21:1814-22. [PMID: 18690722 DOI: 10.1021/tx800161s] [Citation(s) in RCA: 167] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
In vitro covalent binding assessments of drugs have been useful in providing retrospective insights into the association between drug metabolism and a resulting toxicological response. On the basis of these studies, it has been advocated that in vitro covalent binding to liver microsomal proteins in the presence and the absence of NADPH be used routinely to screen drug candidates. However, the utility of this approach in predicting toxicities of drug candidates accurately remains an unanswered question. Importantly, the years of research that have been invested in understanding metabolic bioactivation and covalent binding and its potential role in toxicity have focused only on those compounds that demonstrate toxicity. Investigations have not frequently queried whether in vitro covalent binding could be observed with drugs with good safety records. Eighteen drugs (nine hepatotoxins and nine nonhepatotoxins in humans) were assessed for in vitro covalent binding in NADPH-supplemented human liver microsomes. Of the two sets of nine drugs, seven in each set were shown to undergo some degree of covalent binding. Among hepatotoxic drugs, acetaminophen, carbamazepine, diclofenac, indomethacin, nefazodone, sudoxicam, and tienilic acid demonstrated covalent binding, while benoxaprofen and felbamate did not. Of the nonhepatotoxic drugs evaluated, buspirone, diphenhydramine, meloxicam, paroxetine, propranolol, raloxifene, and simvastatin demonstrated covalent binding, while ibuprofen and theophylline did not. A quantitative comparison of covalent binding in vitro intrinsic clearance did not separate the two groups of compounds, and in fact, paroxetine, a nonhepatotoxin, showed the greatest amount of covalent binding in microsomes. Including factors such as the fraction of total metabolism comprised by covalent binding and the total daily dose of each drug improved the discrimination between hepatotoxic and nontoxic drugs based on in vitro covalent binding data; however, the approach still would falsely identify some agents as potentially hepatotoxic.
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Affiliation(s)
- R Scott Obach
- Pharmacokinetics, Dynamics and Metabolism Department, Pfizer Global Research and Development, Groton, Connecticut 06340, USA.
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Abstract
Liver damage leads to an inflammatory response and to the activation and proliferation of mesenchymal cell populations within the liver which remodel the extracellular matrix as part of an orchestrated wound-healing response. Chronic damage results in a progressive accumulation of scarring proteins (fibrosis) that, with increasing severity, alters tissue structure and function, leading to cirrhosis and liver failure. Efforts to modulate the fibrogenesis process have focused on understanding the biology of the heterogeneous liver fibroblast populations. The fibroblasts are derived from sources within and out with the liver. Fibroblasts expressing alpha-smooth muscle actin (myofibroblasts) may be derived from the transdifferentiation of quiescent hepatic stellate cells. Other fibroblasts emerge from the portal tracts within the liver. At least a proportion of these cells in diseased liver originate from the bone marrow. In addition, fibrogenic fibroblasts may also be generated through liver epithelial (hepatocyte and biliary epithelial cell)-mesenchymal transition. Whatever their origin, it is clear that fibrogenic fibroblast activity is sensitive to (and may be active in) the cytokine and chemokine profiles of liver-resident leucocytes such as macrophages. They may also be a component driving the regeneration of tissue. Understanding the complex intercellular interactions regulating liver fibrogenesis is of increasing importance in view of predicted increases in chronic liver disease and the current paucity of effective therapies.
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Hussaini SH, Farrington EA. Idiosyncratic drug-induced liver injury: an overview. Expert Opin Drug Saf 2007; 6:673-84. [PMID: 17967156 DOI: 10.1517/14740338.6.6.673] [Citation(s) in RCA: 126] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Drug-induced liver injury (DILI) encompasses a spectrum of clinical disease ranging from mild biochemical abnormalities to acute liver failure. The majority of adverse liver reactions are idiosyncratic, occurring in most instances 5-90 days after the causative medication was last taken. The diagnosis of DILI is clinical, based on history, probability of the suspect medication as a cause of liver injury and exclusion of other hepatic disease. DILI can be hepatocellular (predominant rise in alanine transaminase), cholestatic (predominant rise in alkaline phosphatase) or mixed liver injury. An elevated bilirubin level more than twice the upper limit of normal in patients with hepatocellular liver injury implies severe DILI, with a mortality of approximately 10% and with an incidence rate of 0.7-1.3 per 100,000. Although acute liver failure is rare, 13-17% of all acute liver failure cases are attributed to idiosyncratic drug reactions. Response to drug withdrawal may be delayed up to 1 year with cholestatic liver injury with occasional subsequent progressive cholestasis known as the vanishing bile duct syndrome. Overall, chronic disease may occur in up to 6% even if the offending drug is withdrawn. Antibiotics and NSAIDs are the most common cause of DILI. Statins rarely cause significant liver injury whereas antiretroviral therapy is associated with hepatotoxicity in 10% of treated patients. Multiple mechanisms of DILI have been implicated, including TNF-alpha-activated apoptosis, inhibition of mitochondrial function and neoantigen formation. Risk factors for DILI include age, sex and genetic polymorphisms of drug-metabolising enzymes such as cytochrome P450. In patients with human immunodeficiency virus, the presence of chronic viral hepatitis increases the risk of antiretroviral therapy hepatotoxicity. Over the next decade, the combination of accurate case ascertainment of DILI via clinical networks and the application of genomics and proteomics will hopefully lead to accurate prediction of risk of DILI, so that pharmacotherapy can be optimised with avoidance of adverse hepatic events.
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Affiliation(s)
- S Hyder Hussaini
- Royal Cornwall Hospital Trust, Cornwall Gastrointestinal Unit, Truro, TR1 3LJ, UK.
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Umar R, Hassan S, Ladan M, Matazu I, Shehu B, Shehu R, Muhammed L, Molabo F. Adverse Hepatic Effects Associated with Administration of Antiretroviral Drugs (Nevirapine, Lamivudine and Stavudine) to Albino Rats: Implication for Management of Patients with HIV/AIDS. ACTA ACUST UNITED AC 2007. [DOI: 10.3923/ajb.2008.19.25] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Mackay IR. Autoimmune diseases of the liver, autoimmune hepatitis and primary biliary cirrhosis: Unfinished business. Hepatol Res 2007; 37 Suppl 3:S357-64. [PMID: 17931187 DOI: 10.1111/j.1872-034x.2007.00230.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Autoimmune liver diseases (AILD) including autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) have attracted much attention since their discovery 50 years ago, but there remain items of unfinished business. These relate to disease susceptibility including genetic influences (HLA and non-HLA genes, genes associated with female predisposition, and others) and environmental influences (infections, chemicals, xenobiotics and medications). Also needed is better characterization of autoantigenic molecules, particularly the anti-F-actin specificity characteristic of AIH, shown here to have functional effects in vitro. Deeper analysis of T-lymphocyte function in AILD should reveal relative contributions of eachof the multiple subsets of T cells now being defined in studies on laboratory animals, CD4(+), CD8(+), Th1, Th2, Th17, memory subsets and regulatory subsets. Diagnostic immunology providers now offer high-performance assay formats that call for systematic clinical assessments to achieve standardization, calibration and optimal information.
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Affiliation(s)
- Ian R Mackay
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
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Tarantino G, Conca P, Basile V, Gentile A, Capone D, Polichetti G, Leo E. A prospective study of acute drug-induced liver injury in patients suffering from non-alcoholic fatty liver disease. Hepatol Res 2007; 37:410-415. [PMID: 17539815 DOI: 10.1111/j.1872-034x.2007.00072.x] [Citation(s) in RCA: 122] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
AIM Liver damage due to facultative hepatotoxins is scarcely foreseeable. We evaluated the prevalence of acute drug-induced liver injury (DILI) in a specific setting, assessing eventual interactions with pre-existing hepatic illnesses. METHODS The research was carried out in an Italian tertiary care hospital, by analyzing 248 patients with non-advanced liver disease, divided into two well-matched groups: 174 patients (median age 53, 94 females) with hepatitis C virus-related chronic hepatitis; and 74 (median age 55, 39 females) with non-alcoholic fatty liver disease (NAFLD). RESULTS Six patients (2.4% of the whole population) belonging to the NAFLD group (chi(2)-test, P = 0.004) suffered from acute hepatoxicity related to the following drugs, that is antihypertensive, acting on platelet aggregation, antimicrobial, non-steroidal anti-inflammatory and proton pump inhibitor. The NAFLD presence was an independent risk factor in determining drug-related acute hepatitis, with an odds ratio of 3.95 (95% confidence intervals: 11.48-1.35). Central obesity was relevant in every patient with acute toxicity. Alcohol consumption and drug association did not influence the acute drug-induced liver damage. CONCLUSION NAFLD conveys a nearly fourfold increase of DILI risk in obese middle-aged patients. NAFLD, characterized by mitochondrial dysfunction, could predispose to drug-induced hepatotoxicity that probably shares the same pathophysiological mechanism.
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Affiliation(s)
- Giovanni Tarantino
- Department of Clinical and Experimental Medicine, Federico II University Medical School of Naples, Naples, Italy
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GÓMEZ-LECHÓN MJ, CARRASQUER J, BERENGUER J, CASTELL JV. Evidence of antibodies to erythromycin in serum of a patient following an episode of acute drug-induced hepatitis. Clin Exp Allergy 2006. [DOI: 10.1111/j.1365-2222.1996.tb00581.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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