1,214 results match your criteria Annual Review Of Pharmacology And Toxicology[Journal]


Pharmacogenetics of Antiplatelet Therapy.

Annu Rev Pharmacol Toxicol 2022 Aug 1. Epub 2022 Aug 1.

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA; email:

Antiplatelet therapy is used in the treatment of patients with acute coronary syndromes, stroke, and those undergoing percutaneous coronary intervention. Clopidogrel is the most widely used antiplatelet P2Y12 inhibitor in clinical practice. Genetic variation in may influence its enzymatic activity, resulting in individuals who are carriers of loss-of-function alleles and thus have reduced active clopidogrel metabolites, have high on-treatment platelet reactivity and increased ischemic risk. Read More

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Synthetic Cannabinoids: A Pharmacological and Toxicological Overview.

Annu Rev Pharmacol Toxicol 2022 Aug 1. Epub 2022 Aug 1.

Associate Laboratory i4HB - Institute for Health and Bioeconomy, and UCIBIO, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal; email:

Synthetic cannabinoids (SCs) are a chemically diverse group of new psychoactive substances (NPSs) that target the endocannabinoid system, triggering a plethora of actions (e.g., elevated mood sensation, relaxation, appetite stimulation) that resemble, but are more intense than, those induced by cannabis. Read More

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A Delightful Trip Along the Pathway of Cannabinoid and Endocannabinoid Chemistry and Pharmacology.

Annu Rev Pharmacol Toxicol 2022 Jul 18. Epub 2022 Jul 18.

Institute of Drug Research, Medical Faculty, Hebrew University of Jerusalem, Jerusalem, Israel; email:

After a traumatic childhood in Europe during the Second World War, I found that scientific research in Israel was a pleasure beyond my expectations. Over the last 65 year, I have worked on the chemistry and pharmacology of natural products. During the last few decades, most of my research has been on plant cannabinoids, the endogenous cannabinoids arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol, and endogenous anandamide-like compounds, all of which are involved in a wide spectrum of physiological reactions. Read More

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Artificial Intelligence and Machine Learning for Lead-to-Candidate Decision-Making and Beyond.

Authors:
Douglas McNair

Annu Rev Pharmacol Toxicol 2022 Jun 9. Epub 2022 Jun 9.

Global Health, Integrated Development, Bill & Melinda Gates Foundation, Seattle, Washington, USA; email:

The use of artificial intelligence (AI) and machine learning (ML) in pharmaceutical research and development has to date focused on research: target identification; docking-, fragment-, and motif-based generation of compound libraries; modeling of synthesis feasibility; rank-ordering likely hits according to structural and chemometric similarity to compounds having known activity and affinity to the target(s); optimizing a smaller library for synthesis and high-throughput screening; and combining evidence from screening to support hit-to-lead decisions. Applying AI/ML methods to lead optimization and lead-to-candidate (L2C) decision-making has shown slower progress, especially regarding predicting absorption, distribution, metabolism, excretion, and toxicology properties. The present review surveys reasons why this is so, reports progress that has occurred in recent years, and summarizes some of the issues that remain. Read More

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Prenatal and Postnatal Pharmacotherapy in Down Syndrome: The Search to Prevent or Ameliorate Neurodevelopmental and Neurodegenerative Disorders.

Annu Rev Pharmacol Toxicol 2022 01;62:211-233

Department of Neurosciences, University of California, San Diego, La Jolla, California 92093, USA; email:

Those with Down syndrome (DS)-trisomy for chromosome 21-are routinely impacted by cognitive dysfunction and behavioral challenges in children and adults and Alzheimer's disease in older adults. No proven treatments specifically address these cognitive or behavioral changes. However, advances in the establishment of rodent models and human cell models promise to support development of such treatments. Read More

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January 2022

Central Nervous System Control of Glucose Homeostasis: A Therapeutic Target for Type 2 Diabetes?

Annu Rev Pharmacol Toxicol 2022 01;62:55-84

UW Medicine Diabetes Institute, Department of Medicine, University of Washington, Seattle, Washington 98109, USA; email:

Historically, pancreatic islet beta cells have been viewed as principal regulators of glycemia, with type 2 diabetes (T2D) resulting when insulin secretion fails to compensate for peripheral tissue insulin resistance. However, glycemia is also regulated by insulin-independent mechanisms that are dysregulated in T2D. Based on evidence supporting its role both in adaptive coupling of insulin secretion to changes in insulin sensitivity and in the regulation of insulin-independent glucose disposal, the central nervous system (CNS) has emerged as a fundamental player in glucose homeostasis. Read More

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January 2022

Patient Centricity Driving Formulation Innovation: Improvements in Patient Care Facilitated by Novel Therapeutics and Drug Delivery Technologies.

Annu Rev Pharmacol Toxicol 2022 01;62:341-363

Pharma Technical Development, Roche TCRC Inc., Little Falls, New Jersey 07424, USA.

Innovative formulation technologies can play a crucial role in transforming a novel molecule to a medicine that significantly enhances patients' lives. Improved mechanistic understanding of diseases has inspired researchers to expand the druggable space using new therapeutic modalities such as interfering RNA, protein degraders, and novel formats of monoclonal antibodies. Sophisticated formulation strategies are needed to deliver the drugs to their sites of action and to achieve patient centricity, exemplified by messenger RNA vaccines and oral peptides. Read More

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January 2022

Oxidative Stress and Metabolism: A Mechanistic Insight for Glyphosate Toxicology.

Annu Rev Pharmacol Toxicol 2022 01;62:617-639

Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, and Research Institute Hospital 12 de Octubre, 28040 Madrid, Spain; email:

Glyphosate (GLYP) is a widely used pesticide; it is considered to be a safe herbicide for animals and humans because it targets 5-enolpyruvylshikimate-3-phosphate synthase. However, there has been increasing evidence that GLYP causes varying degrees of toxicity. Moreover, oxidative stress and metabolism are highly correlated with toxicity. Read More

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January 2022

Brain-Protective Mechanisms of Transcription Factor NRF2: Toward a Common Strategy for Neurodegenerative Diseases.

Authors:
Antonio Cuadrado

Annu Rev Pharmacol Toxicol 2022 01 12;62:255-277. Epub 2021 Oct 12.

Department of Biochemistry, Medical College, Autonomous University of Madrid, Madrid 28049, Spain.

Neurodegenerative diseases are characterized by the loss of homeostatic functions that control redox and energy metabolism, neuroinflammation, and proteostasis. The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is a master controller of these functions, and its overall activity is compromised during aging and in these diseases. However, NRF2 can be activated pharmacologically and is now being considered a common therapeutic target. Read More

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January 2022

Introduction to the Theme "New Insights, Strategies, and Therapeutics for Common Diseases".

Annu Rev Pharmacol Toxicol 2022 01 4;62:19-24. Epub 2021 Oct 4.

Biozentrum, University of Basel, CH-4056 Basel, Switzerland.

The reviews in Volume 62 of the () cover a diverse range of topics. A theme that encompasses many of these reviews is their relevance to common diseases and disorders, including type 2 diabetes, heart failure, cancer, tuberculosis, Alzheimer's disease, neurodegenerative disorders, and Down syndrome. Other reviews highlight important aspects of therapeutics, including placebos and patient-centric approaches to drug formulation. Read More

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January 2022

Emerging Therapeutics, Technologies, and Drug Development Strategies to Address Patient Nonadherence and Improve Tuberculosis Treatment.

Annu Rev Pharmacol Toxicol 2022 01 30;62:197-210. Epub 2021 Sep 30.

Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California 94158, USA; email:

Imperfect medication adherence remains the biggest predictor of treatment failure for patients with tuberculosis. Missed doses during treatment lead to relapse, tuberculosis resistance, and further spread of disease. Understanding individual patient phenotypes, population pharmacokinetics, resistance development, drug distribution to tuberculosis lesions, and pharmacodynamics at the site of infection is necessary to fully measure the impact of adherence on patient outcomes. Read More

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January 2022

Repurposing Colchicine for Heart Disease.

Annu Rev Pharmacol Toxicol 2022 01 30;62:121-129. Epub 2021 Sep 30.

Montreal Heart Institute, Montreal, Quebec H1T 1C8, Canada; email:

Colchicine is one of the most ancient medications still prescribed. It is extracted from the plant and is routinely used because of its broad anti-inflammatory properties to treat gout and familial Mediterranean fever. Colchicine has shown efficacy in various clinical settings in which inflammation is a key component, and it has become first-line therapy for acute and recurrent pericarditis. Read More

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January 2022

Systems Biology of the Vasopressin V2 Receptor: New Tools for Discovery of Molecular Actions of a GPCR.

Annu Rev Pharmacol Toxicol 2022 01 27;62:595-616. Epub 2021 Sep 27.

Epithelial Systems Biology Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20814, USA; email:

Systems biology can be defined as the study of a biological process in which all of the relevant components are investigated together in parallel to discover the mechanism. Although the approach is not new, it has come to the forefront as a result of genome sequencing projects completed in the first few years of the current century. It has elements of large-scale data acquisition (chiefly next-generation sequencing-based methods and protein mass spectrometry) and large-scale data analysis (big data integration and Bayesian modeling). Read More

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January 2022

Precision Medicine Approaches for Infantile-Onset Developmental and Epileptic Encephalopathies.

Annu Rev Pharmacol Toxicol 2022 01 27;62:641-662. Epub 2021 Sep 27.

Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia; email:

Epilepsy is an etiologically heterogeneous condition; however, genetic factors are thought to play a role in most patients. For those with infantile-onset developmental and epileptic encephalopathy (DEE), a genetic diagnosis is now obtained in more than 50% of patients. There is considerable motivation to utilize these molecular diagnostic data to help guide treatment, as children with DEEs often have drug-resistant seizures as well as developmental impairment related to cerebral epileptiform activity. Read More

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January 2022

Endocrine-Disrupting Chemicals and Child Health.

Annu Rev Pharmacol Toxicol 2022 01 23;62:573-594. Epub 2021 Sep 23.

Departments of Pediatrics and Environmental Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA; email:

While definitions vary, endocrine-disrupting chemicals (EDCs) have two fundamental features: their disruption of hormone function and their contribution to disease and disability. The unique vulnerability of children to low-level EDC exposures has eroded the notion that only the dose makes the thing a poison, requiring a paradigm shift in scientific and policy practice. In this review, we discuss the unique vulnerability of children as early as fetal life and provide an overview of epidemiological studies on programming effects of EDCs on neuronal, metabolic, and immune pathways as well as on endocrine, reproductive, and renal systems. Read More

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January 2022

E-Cigarette Toxicology.

Annu Rev Pharmacol Toxicol 2022 01 23;62:301-322. Epub 2021 Sep 23.

Department of Environmental Medicine, NYU School of Medicine, New York, NY 10010, USA; email:

Since the spread of tobacco from the Americas hundreds of years ago, tobacco cigarettes and, more recently, alternative tobacco products have become global products of nicotine addiction. Within the evolving alternative tobacco product space, electronic cigarette (e-cigarette) vaping has surpassed conventional cigarette smoking among adolescents and young adults in the United States and beyond. This review describes the experimental and clinical evidence of e-cigarette toxicity and deleterious health effects. Read More

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January 2022

Chemogenetic Approaches to Probe Redox Pathways: Implications for Cardiovascular Pharmacology and Toxicology.

Annu Rev Pharmacol Toxicol 2022 01 16;62:551-571. Epub 2021 Sep 16.

Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA; email:

Chemogenetics refers to experimental systems that dynamically regulate the activity of a recombinant protein by providing or withholding the protein's specific biochemical stimulus. Chemogenetic tools permit precise dynamic control of specific signaling molecules to delineate the roles of those molecules in physiology and disease. Yeast d-amino acid oxidase (DAAO) enables chemogenetic manipulation of intracellular redox balance by generating hydrogen peroxide only in the presence of d-amino acids. Read More

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January 2022

Noncanonical Metabotropic Glutamate Receptor 5 Signaling in Alzheimer's Disease.

Annu Rev Pharmacol Toxicol 2022 01 13;62:235-254. Epub 2021 Sep 13.

University of Ottawa Brain and Mind Research Institute and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada; email:

Metabotropic glutamate receptor 5 (mGluR5) is ubiquitously expressed in brain regions responsible for memory and learning. It plays a key role in modulating rapid changes in synaptic transmission and plasticity. mGluR5 supports long-term changes in synaptic strength by regulating the transcription and translation of essential synaptic proteins. Read More

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January 2022

Synthetic Retinoids Beyond Cancer Therapy.

Authors:
Lorraine J Gudas

Annu Rev Pharmacol Toxicol 2022 01 13;62:155-175. Epub 2021 Sep 13.

Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; email:

While the uses of retinoids for cancer treatment continue to evolve, this review focuses on other therapeutic areas in which retinoids [retinol (vitamin A), all- retinoic acid (RA), and synthetic retinoic acid receptor (RAR)α-, β-, and γ-selective agonists] are being used and on promising new research that suggests additional uses for retinoids for the treatment of disorders of the kidneys, skeletal muscles, heart, pancreas, liver, nervous system, skin, and other organs. The most mature area, in terms of US Food and Drug Administration-approved, RAR-selective agonists, is for treatment of various skin diseases. Synthetic retinoid agonists have major advantages over endogenous RAR agonists such as RA. Read More

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January 2022

Endocannabinoid-Based Therapies.

Annu Rev Pharmacol Toxicol 2022 01 13;62:483-507. Epub 2021 Sep 13.

Department of Anatomy and Neurobiology, University of California, Irvine, California 92697, USA; email:

The endocannabinoids are lipid-derived messengers that play a diversity of regulatory roles in mammalian physiology. Dysfunctions in their activity have been implicated in various disease conditions, attracting attention to the endocannabinoid system as a possible source of therapeutic drugs. This signaling complex has three components: the endogenous ligands, anandamide and 2-arachidonoyl--glycerol (2-AG); a set of enzymes and transporters that generate, eliminate, or modify such ligands; and selective cell surface receptors that mediate their biological actions. Read More

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January 2022

HLA Allele-Restricted Immune-Mediated Adverse Drug Reactions: Framework for Genetic Prediction.

Annu Rev Pharmacol Toxicol 2022 01 13;62:509-529. Epub 2021 Sep 13.

MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GL, United Kingdom; email:

Human leukocyte antigen (HLA) is a hallmark genetic marker for the prediction of certain immune-mediated adverse drug reactions (ADRs). Numerous basic and clinical research studies have provided the evidence base to push forward the clinical implementation of HLA testing for the prevention of such ADRs in susceptible patients. This review explores current translational progress in using HLA as a key susceptibility factor for immune ADRs and highlights gaps in our knowledge. Read More

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January 2022

KCNQ Potassium Channels as Targets of Botanical Folk Medicines.

Annu Rev Pharmacol Toxicol 2022 01 13;62:447-464. Epub 2021 Sep 13.

Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California 92697, USA; email:

Since prehistory, human species have depended on plants for both food and medicine. Even in countries with ready access to modern medicines, alternative treatments are still highly regarded and commonly used. Unlike modern pharmaceuticals, many botanical medicines are in widespread use despite a lack of safety and efficacy data derived from controlled clinical trials and often unclear mechanisms of action. Read More

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January 2022

Sodium-Glucose Cotransporter 2 Inhibitors in Heart Failure.

Annu Rev Pharmacol Toxicol 2022 01 13;62:109-120. Epub 2021 Sep 13.

Division of Cardiovascular Medicine, University of Utah Health, Salt Lake City, Utah 84132, USA; email:

Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve blood glucose control by blocking renal glucose reabsorption with little subsequent risk of hypoglycemia. Consequently, there are decreases in plasma volume, body weight, and blood pressure. Additional putative benefits include improved cardiovascular energetics, decreased systemic inflammation, and less renal dysfunction. Read More

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January 2022

Measuring Pharmacogene Variant Function at Scale Using Multiplexed Assays.

Annu Rev Pharmacol Toxicol 2022 01 13;62:531-550. Epub 2021 Sep 13.

Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA; email:

As costs of next-generation sequencing decrease, identification of genetic variants has far outpaced our ability to understand their functional consequences. This lack of understanding is a central challenge to a key promise of pharmacogenomics: using genetic information to guide drug selection and dosing. Recently developed multiplexed assays of variant effect enable experimental measurement of the function of thousands of variants simultaneously. Read More

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January 2022

Targeting NRF2 and Its Downstream Processes: Opportunities and Challenges.

Annu Rev Pharmacol Toxicol 2022 01 9;62:279-300. Epub 2021 Sep 9.

Department of Cancer Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA; email:

The transcription factor NRF2 coordinates the expression of a vast array of cytoprotective and metabolic genes in response to various stress inputs to restore cellular homeostasis. Transient activation of NRF2 in healthy tissues has been long recognized as a cellular defense mechanism and is critical to prevent cancer initiation by carcinogens. However, cancer cells frequently hijack the protective capability of NRF2 to sustain the redox balance and meet their metabolic requirements for proliferation. Read More

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January 2022

Fragile X Syndrome: Lessons Learned and What New Treatment Avenues Are on the Horizon.

Annu Rev Pharmacol Toxicol 2022 01 9;62:365-381. Epub 2021 Sep 9.

MIND Institute, University of California Davis Health, Sacramento, California 95817, USA.

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and the leading single-gene form of autism spectrum disorder, encompassing cognitive, behavioral, and physical forms of clinical involvement. FXS is caused by large expansions of a noncoding CGG repeat (>200 repeats) in the gene, at which point the gene is generally silenced. Absence of protein (FMRP), important for synaptic development and maintenance, gives rise to the neurodevelopmental disorder. Read More

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January 2022

Pharmacology of TRPC Channels and Its Potential in Cardiovascular and Metabolic Medicine.

Annu Rev Pharmacol Toxicol 2022 01 9;62:427-446. Epub 2021 Sep 9.

Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9JT, United Kingdom; email:

Transient receptor potential canonical (TRPC) proteins assemble to form homo- or heterotetrameric, nonselective cation channels permeable to K, Na, and Ca. TRPC channels are thought to act as complex integrators of physical and chemical environmental stimuli. Although the understanding of essential physiological roles of TRPC channels is incomplete, their implication in various pathological mechanisms and conditions of the nervous system, kidneys, and cardiovascular system in combination with the lack of major adverse effects of TRPC knockout or TRPC channel inhibition is driving the search of TRPC channel modulators as potential therapeutics. Read More

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January 2022

Drug Target Identification in Tissues by Thermal Proteome Profiling.

Annu Rev Pharmacol Toxicol 2022 01 9;62:465-482. Epub 2021 Sep 9.

Genome Biology Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany; email:

Drug target deconvolution can accelerate the drug discovery process by identifying a drug's targets (facilitating medicinal chemistry efforts) and off-targets (anticipating toxicity effects or adverse drug reactions). Multiple mass spectrometry-based approaches have been developed for this purpose, but thermal proteome profiling (TPP) remains to date the only one that does not require compound modification and can be used to identify intracellular targets in living cells. TPP is based on the principle that the thermal stability of a protein can be affected by its interactions. Read More

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January 2022

Aryl Hydrocarbon Receptor and Its Diverse Ligands and Functions: An Exposome Receptor.

Annu Rev Pharmacol Toxicol 2022 01 9;62:383-404. Epub 2021 Sep 9.

INSERM UMR-S1124, T3S, Toxicologie Environnementale, Cibles thérapeutiques, Signalisation cellulaire et Biomarqueurs, and Université de Paris, 75006 Paris, France; email:

The aryl hydrocarbon receptor (AhR) is a transcriptional factor that regulates multiple functions following its activation by a variety of ligands, including xenobiotics, natural products, microbiome metabolites, and endogenous molecules. Because of this diversity, the AhR constitutes an exposome receptor. One of its main functions is to regulate several lines of defense against chemical insults and bacterial infections. Read More

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January 2022

Non-P450 Drug-Metabolizing Enzymes: Contribution to Drug Disposition, Toxicity, and Development.

Annu Rev Pharmacol Toxicol 2022 01 9;62:405-425. Epub 2021 Sep 9.

Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, and WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan; email:

Most clinically used drugs are metabolized in the body via oxidation, reduction, or hydrolysis reactions, which are considered phase I reactions. Cytochrome P450 (P450) enzymes, which primarily catalyze oxidation reactions, contribute to the metabolism of over 50% of clinically used drugs. In the last few decades, the function and regulation of P450s have been extensively studied, whereas the characterization of non-P450 phase I enzymes is still incomplete. Read More

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January 2022