Abstract
Drug-induced liver injury (DILI) has become a leading cause of severe liver disease in Western countries and therefore poses a major clinical and regulatory challenge. Whereas previously drug-specific pathways leading to initial injury of liver cells were the main focus of mechanistic research and classifications, current concepts see these as initial upstream events and appreciate that subsequent common downstream pathways and their attenuation by drugs and other environmental and genetic factors also have a profound impact on the risk of an individual patient to develop overt liver disease. This review summarizes current mechanistic concepts of DILI in a 3-step model that limits its principle mechanisms to three main ways of initial injury, i.e. direct cell stress, direct mitochondrial impairment, and specific immune reactions. Subsequently, initial injury initiates further downstream events, i.e. direct and death receptor-mediated pathways leading to mitochondrial permeability transition, which then results in apoptotic or necrotic cell death. For all mechanisms, mitochondria play a central role in events leading to apoptotic vs. necrotic cell death. New treatment targets consequently focus on interference with downstream pathways that mediate injury and therefore determine the ultimate outcome of DILI. Genome wide and targeted pharmacogenetic as well as metabonomic approaches are now used in order to reach the key goals of a better understanding of mechanisms in hepatotoxicity, and to develop new strategies for its prediction and treatment. However, the complexity of interactions between genetic and environmental risk factors is considerable, and DILI therefore currently remains unpredictable for most hepatotoxins.
Keywords: Acetaminophen, apoptosis, drug-induced liver injury, drug metabolism, Fas, glutathione, hepatotoxicity, metabonomics, mitochondria, mitochondrial permeability transition
Current Medicinal Chemistry
Title: Current Concepts of Mechanisms in Drug-Induced Hepatotoxicity
Volume: 16 Issue: 23
Author(s): Stefan Russmann, Gerd A. Kullak-Ublick and Ignazio Grattagliano
Affiliation:
Keywords: Acetaminophen, apoptosis, drug-induced liver injury, drug metabolism, Fas, glutathione, hepatotoxicity, metabonomics, mitochondria, mitochondrial permeability transition
Abstract: Drug-induced liver injury (DILI) has become a leading cause of severe liver disease in Western countries and therefore poses a major clinical and regulatory challenge. Whereas previously drug-specific pathways leading to initial injury of liver cells were the main focus of mechanistic research and classifications, current concepts see these as initial upstream events and appreciate that subsequent common downstream pathways and their attenuation by drugs and other environmental and genetic factors also have a profound impact on the risk of an individual patient to develop overt liver disease. This review summarizes current mechanistic concepts of DILI in a 3-step model that limits its principle mechanisms to three main ways of initial injury, i.e. direct cell stress, direct mitochondrial impairment, and specific immune reactions. Subsequently, initial injury initiates further downstream events, i.e. direct and death receptor-mediated pathways leading to mitochondrial permeability transition, which then results in apoptotic or necrotic cell death. For all mechanisms, mitochondria play a central role in events leading to apoptotic vs. necrotic cell death. New treatment targets consequently focus on interference with downstream pathways that mediate injury and therefore determine the ultimate outcome of DILI. Genome wide and targeted pharmacogenetic as well as metabonomic approaches are now used in order to reach the key goals of a better understanding of mechanisms in hepatotoxicity, and to develop new strategies for its prediction and treatment. However, the complexity of interactions between genetic and environmental risk factors is considerable, and DILI therefore currently remains unpredictable for most hepatotoxins.
Export Options
About this article
Cite this article as:
Russmann Stefan, Kullak-Ublick A. Gerd and Grattagliano Ignazio, Current Concepts of Mechanisms in Drug-Induced Hepatotoxicity, Current Medicinal Chemistry 2009; 16 (23) . https://dx.doi.org/10.2174/092986709788803097
DOI https://dx.doi.org/10.2174/092986709788803097 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Point of Care Cardiac Ultrasound Applications in the Emergency Department and Intensive Care Unit - A Review
Current Cardiology Reviews Molecular Targets of Diabetic Cardiovascular Complications
Current Drug Targets Augmentation Therapy with Alpha1-antitrypsin: Novel Perspectives
Cardiovascular & Hematological Disorders-Drug Targets Emerging Roles for Vasoactive Peptides in Diagnostic and Therapeutic Strategies Against Atherosclerotic Cardiovascular Diseases
Current Protein & Peptide Science Neonatal Systemic Thrombosis: An Updated Overview
Current Vascular Pharmacology Potential Role of IL-18 in the Immunopathogenesis of AIDS, HIVAssociated Lipodystrophy and Related Clinical Conditions
Current HIV Research Not a Painless Condition: Rheumatological and Musculoskeletal Symptoms in Type 2 Diabetes, and the Implications for Exercise Participation
Current Diabetes Reviews Therapeutic Targeting of P-Selectin in Atherosclerosis
Inflammation & Allergy - Drug Targets (Discontinued) Magnesium as a Neuroprotective Agent in Cerebral Ischemia
Current Medicinal Chemistry - Central Nervous System Agents New Technological Developments in the Clinical Imaging of Atherosclerotic Plaque
Current Pharmaceutical Design Acute Severe Arterial Hypertension: Therapeutic Options
Current Drug Targets Multifunctionalized Microbubbles for Cancer Diagnosis and Therapy
Anti-Cancer Agents in Medicinal Chemistry Antiplatelet and Antithrombin Strategies in Acute Coronary Syndrome: State-Of-The-Art Review
Current Cardiology Reviews High Sensitivity C-Reactive Protein (hsCRP): A New Biochemical Marker of Atherosclerotic Vascular Disease
Current Cardiology Reviews Current Management of Fetal and Neonatal Renal Tumors
Current Pediatric Reviews Diabetes Mellitus and SARS-CoV-2 Infection: Pathophysiologic Mechanisms and Implications in Management
Current Diabetes Reviews Inflammation in Ischemic Stroke Subtypes
Current Pharmaceutical Design Role of Vitamin D in Vascular Complications and Vascular Access Outcome in Patients with Chronic Kidney Disease
Current Medicinal Chemistry Towards More Efficient Glutathione Peroxidase Mimics: Substrate Recognition and Catalytic Group Assembly
Current Medicinal Chemistry Dysfunctions of the Diffusional Membrane Pathways Mediated Hemichannels in Inherited and Acquired Human Diseases
Current Vascular Pharmacology