Abstract
Over the past decades, it has become abundantly clear that enzymes evolved to detoxify and eliminate foreign chemicals from the body, occasionally generate highly reactive metabolites which have toxicological implications. To decrease the probability of late clinical failure or market withdrawal, there has been an increased prioritization on understanding key metabolic processes that might cause drug interactions or toxicities. Significant advances have been made in the detection of reactive metabolites and in understanding the structure activity relationship. It is now widely accepted that compounds with certain functional groups such as anilines, quinones, hydrazines, thiophenes, furans, acylpropionic acids, and alkynes have a much greater associated risk towards formation of reactive metabolites than compounds that do not contain such “structural alerts”. Detection of reactive metabolites is usually done with in vitro assays, which have become more sensitive with advances in mass spectrometry. As an increasingly large number of compounds that form reactive metabolites have been identified, much of the focus has shifted from detection to evaluation of toxicological implication. While there is a disproportionate number of compounds metabolized to reactive metabolites that are associated with drug-induced hepatotoxicity and serious skin toxicities such as toxic endothelial necrolysis and Steven’s Johnson syndrome, attempts to predict toxicity based on in vitro testing have been discouraging. In this review we attempt to summarize the experimental options available to evaluate reactive metabolites.
Keywords: Bioactivation, cytochrome P450, hepatotoxicity, reactive metabolites.
Current Medicinal Chemistry
Title:Gauging Reactive Metabolites in Drug-Induced Toxicity
Volume: 22 Issue: 4
Author(s): Marsha R. Eno and Michael D. Cameron
Affiliation:
Keywords: Bioactivation, cytochrome P450, hepatotoxicity, reactive metabolites.
Abstract: Over the past decades, it has become abundantly clear that enzymes evolved to detoxify and eliminate foreign chemicals from the body, occasionally generate highly reactive metabolites which have toxicological implications. To decrease the probability of late clinical failure or market withdrawal, there has been an increased prioritization on understanding key metabolic processes that might cause drug interactions or toxicities. Significant advances have been made in the detection of reactive metabolites and in understanding the structure activity relationship. It is now widely accepted that compounds with certain functional groups such as anilines, quinones, hydrazines, thiophenes, furans, acylpropionic acids, and alkynes have a much greater associated risk towards formation of reactive metabolites than compounds that do not contain such “structural alerts”. Detection of reactive metabolites is usually done with in vitro assays, which have become more sensitive with advances in mass spectrometry. As an increasingly large number of compounds that form reactive metabolites have been identified, much of the focus has shifted from detection to evaluation of toxicological implication. While there is a disproportionate number of compounds metabolized to reactive metabolites that are associated with drug-induced hepatotoxicity and serious skin toxicities such as toxic endothelial necrolysis and Steven’s Johnson syndrome, attempts to predict toxicity based on in vitro testing have been discouraging. In this review we attempt to summarize the experimental options available to evaluate reactive metabolites.
Export Options
About this article
Cite this article as:
Eno R. Marsha and Cameron D. Michael, Gauging Reactive Metabolites in Drug-Induced Toxicity, Current Medicinal Chemistry 2015; 22 (4) . https://dx.doi.org/10.2174/0929867321666140826113520
DOI https://dx.doi.org/10.2174/0929867321666140826113520 |
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
-
An Update on the Roles of the Complement System in Autoimmune Diseases and the Therapeutic Possibilities of Anti-Complement Agents
Current Drug Therapy STING Activation and its Application in Immuno-Oncology
Current Topics in Medicinal Chemistry MCP-1/CCL2 as a Therapeutic Target in Myocardial Infarction and Ischemic Cardiomyopathy
Inflammation & Allergy - Drug Targets (Discontinued) The Perfect Storm: A Rheumatologist's Point of View on COVID-19 Infection
Current Rheumatology Reviews Imatinib Mesylate (Gleevec©): Targeted Therapy Against Cancer with Immune Properties
Endocrine, Metabolic & Immune Disorders - Drug Targets Involvement of Coagulation and Hemostasis in Inflammatory Bowel Diseases
Current Vascular Pharmacology Myocardial Inflammation in Autoimmune Diseases: Investigation by Cardiovascular Magnetic Resonance and Endomyocardial Biopsy
Inflammation & Allergy - Drug Targets (Discontinued) Therapeutic Implications of Tocilizumab, A Humanized Anti-Interleukin-6 Receptor Antibody, for Various Immune-Mediated Diseases: An Update Review
Current Rheumatology Reviews Novel Systemic Drugs for Cutaneous T-Cell Lymphoma
Recent Patents on Anti-Cancer Drug Discovery The Role of Endothelin System in Cardiovascular Disease and the Potential Therapeutic Perspectives of its Inhibition
Current Topics in Medicinal Chemistry Remodelling of the Ca2+ Toolkit in Tumor Endothelium as a Crucial Responsible for the Resistance to Anticancer Therapies
Current Signal Transduction Therapy Anti-TNF-α Antibody Therapies in Autoimmune Diseases
Current Topics in Medicinal Chemistry Prevention of Endothelial Dysfunction and Cardiovascular Disease by n-3 Fatty Acids-Inhibiting Action on Oxidative Stress and Inflammation
Current Pharmaceutical Design Transcranial Doppler Ultrasonography: Current Status
Current Medical Imaging Outcomes of Anticoagulant Therapy with Low-Molecular-Weight Heparin (LMWH) and Warfarin for Thromboangiitis Obliterans (TAO)
Current Vascular Pharmacology Resveratrol and Cardiovascular Disease
Current Nutrition & Food Science Successful Treatment of Pulmonary Hemorrhage Associated with Pediatric Tsutsugamushi Disease by Chloromycetin
Current Signal Transduction Therapy Atypical Manifestations of Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Children: A Systematic Review
Current Pediatric Reviews ATP Binding Cassette Transporter A1 (ABCA1) Associated Proteins:Potential Drug Targets in the Metabolic Syndrome and Atherosclerotic Disease?
Current Pharmaceutical Biotechnology Computational Development of Selective nNOS Inhibitors: Binding Modes and Pharmacokinetic Considerations
Current Medicinal Chemistry