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Drug Metabolism and Disposition: the... Aug 2018Drug-induced cardiotoxicity may be modulated by endogenous arachidonic acid (AA)-derived metabolites known as epoxyeicosatrienoic acids (EETs) synthesized by cytochrome... (Review)
Review
Drug-induced cardiotoxicity may be modulated by endogenous arachidonic acid (AA)-derived metabolites known as epoxyeicosatrienoic acids (EETs) synthesized by cytochrome P450 2J2 (CYP2J2). The biologic effects of EETs, including their protective effects on inflammation and vasodilation, are diverse because, in part, of their ability to act on a variety of cell types. In addition, CYP2J2 metabolizes both exogenous and endogenous substrates and is involved in phase 1 metabolism of a variety of structurally diverse compounds, including some antihistamines, anticancer agents, and immunosuppressants. This review addresses current understanding of the role of CYP2J2 in the metabolism of xenobiotics and endogenous AA, focusing on the effects on the cardiovascular system. In particular, we have promoted here the hypothesis that CYP2J2 influences drug-induced cardiotoxicity through potentially conflicting effects on the production of protective EETs and the metabolism of drugs.
Topics: Animals; Cardiotoxicity; Cardiovascular System; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Humans; Inactivation, Metabolic; Metabolic Clearance Rate; Xenobiotics
PubMed: 29695613
DOI: 10.1124/dmd.117.078964 -
Current Protein & Peptide Science 2017Glucose and lipid are the major energy sources, and pivotal components of organic metabolism in mammals. Inappropriate diet directly influences the metabolic rate, and... (Review)
Review
Glucose and lipid are the major energy sources, and pivotal components of organic metabolism in mammals. Inappropriate diet directly influences the metabolic rate, and can alter the body's homeostasis. The underlying changes in energy storage and utilization would manifest as metabolic syndrome including obesity and high blood pressure, and high blood glucose, which are predisposing factors that significantly increase the risk for cardiovascular diseases and Type 2 Diabetes (T2D). Thus, it is essential to identify the genes that are involved in the process of glucose and lipid metabolism. Utilizing current advanced scientific methodology and technology, as well as computational resources has led to discovery of many novel genes with major roles in energy metabolism. In addition, many studies have focused on the functional analysis of the novel genes. Nowadays, uncovering the genes that are involved in glucose and lipid storage and utilization, as well as underlying pathways that regulate expression of those genes is an area of ongoing research. Here, we summarize the current research related to the novel genes regulating glucose and lipid metabolisms, which enable us to develop more efficient means of prevention and management of metabolic diseases such as T2D, obesity, high blood glucose, and hypertension.
Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Energy Metabolism; Gene Expression Regulation; Glucose; Humans; Lipid Metabolism; Lipids; Obesity
PubMed: 27356932
DOI: 10.2174/1389203717666160627084304 -
Nutrients Nov 2021Diabetes remains one of the leading causes of deaths and co-morbidities in the world, with tremendous human, social and economic costs. Therefore, despite therapeutics... (Review)
Review
Diabetes remains one of the leading causes of deaths and co-morbidities in the world, with tremendous human, social and economic costs. Therefore, despite therapeutics and technological advancements, improved strategies to tackle diabetes management are still needed. One of the suggested strategies is the consumption of (poly)phenols. Positive outcomes of dietary (poly)phenols have been pointed out towards different features in diabetes. This is the case of ellagitannins, which are present in numerous foodstuffs such as pomegranate, berries, and nuts. Ellagitannins have been reported to have a multitude of effects on metabolic diseases. However, these compounds have high molecular weight and do not reach circulation at effective concentrations, being metabolized in smaller compounds. After being metabolized into ellagic acid in the small intestine, the colonic microbiota hydrolyzes and metabolizes ellagic acid into dibenzopyran-6-one derivatives, known as urolithins. These low molecular weight compounds reach circulation in considerable concentrations ranging until micromolar levels, capable of reaching target tissues. Different urolithins are formed throughout the metabolization process, but urolithin A, isourolithin A, and urolithin B, and their phase-II metabolites are the most frequent ones. In recent years, urolithins have been the focus of attention in regard to their effects on a multiplicity of chronic diseases, including cancer and diabetes. In this review, we will discuss the latest advances about the protective effects of urolithins on diabetes.
Topics: Biological Availability; Coumarins; Diabetes Mellitus; Fruit; Humans; Hydrolyzable Tannins; Nuts; Pomegranate; Protective Agents
PubMed: 34959837
DOI: 10.3390/nu13124285 -
Journal of Personalized Medicine Jul 2023Due to the chronic relapsing nature of mental disorders and increased life expectancy, the societal burden of these non-communicable diseases will increase even further.... (Review)
Review
Due to the chronic relapsing nature of mental disorders and increased life expectancy, the societal burden of these non-communicable diseases will increase even further. Treatments for mental disorders, such as depression, are available, but their effect is limited due to patients' (genetic) heterogeneity, low treatment compliance and frequent side effects. In general, only one-third of the patients respond to treatment. Today, medication selection in psychiatry relies on a trial-and-error approach based mainly on physicians' experience. Pharmacogenetic (PGx) testing can help in this process by determining the person-specific genetic factors that may predict clinical response and side effects associated with genetic variants that impact drug-metabolizing enzymes, drug transporters or drug targets. PGxis a discipline that investigates genetic factors that affect the absorption, metabolism, and transport of drugs, thereby affecting therapy outcome. These genetic factors can, among other things, lead to differences in the activity of enzymes that metabolize drugs. Studies in depressed patients show that genotyping of drug-metabolizing enzymes can increase the effectiveness of treatment, which could benefit millions of patients worldwide. This review highlights these studies, gives recommendations and provides future perspectives on how to proceed with PGx testing. Finally, it is recommended to consider genotyping for and , when there is an indication (side effects or inefficacy).
PubMed: 37511796
DOI: 10.3390/jpm13071183 -
Frontiers in Immunology 2024Excess dietary fructose consumption has been long proposed as a culprit for the world-wide increase of incidence in metabolic disorders and cancer within the past... (Review)
Review
Excess dietary fructose consumption has been long proposed as a culprit for the world-wide increase of incidence in metabolic disorders and cancer within the past decades. Understanding that cancer cells can gradually accumulate metabolic mutations in the tumor microenvironment, where glucose is often depleted, this raises the possibility that fructose can be utilized by cancer cells as an alternative source of carbon. Indeed, recent research has increasingly identified various mechanisms that show how cancer cells can metabolize fructose to support their proliferating and migrating needs. In light of this growing interest, this review will summarize the recent advances in understanding how fructose can metabolically reprogram different types of cancer cells, as well as how these metabolic adaptations can positively support cancer cells development and malignancy.
Topics: Humans; Fructose; Neoplasms; Tumor Microenvironment; Animals; Cellular Reprogramming; Energy Metabolism; Metabolic Reprogramming
PubMed: 38711514
DOI: 10.3389/fimmu.2024.1375461 -
International Journal of Molecular... Oct 2020In vitro methods which incorporate metabolic capability into the assays allow us to assess the activity of metabolites from their parent compounds. These methods can be... (Review)
Review
In vitro methods which incorporate metabolic capability into the assays allow us to assess the activity of metabolites from their parent compounds. These methods can be applied into high-throughput screening (HTS) platforms, thereby increasing the speed to identify compounds that become active via the metabolism process. HTS was originally used in the pharmaceutical industry and now is also used in academic settings to evaluate biological activity and/or toxicity of chemicals. Although most chemicals are metabolized in our body, many HTS assays lack the capability to determine compound activity via metabolism. To overcome this problem, several in vitro metabolic methods have been applied to an HTS format. In this review, we describe in vitro metabolism methods and their application in HTS assays, as well as discuss the future perspectives of HTS with metabolic activity. Each in vitro metabolism method has advantages and disadvantages. For instance, the S9 mix has a full set of liver metabolic enzymes, but it displays high cytotoxicity in cell-based assays. In vitro metabolism requires liver fractions or the use of other metabolically capable systems, including primary hepatocytes or recombinant enzymes. Several newly developed in vitro metabolic methods, including HepaRG cells, three-dimensional (3D) cell models, and organ-on-a-chip technology, will also be discussed. These newly developed in vitro metabolism approaches offer significant progress in dissecting biological processes, developing drugs, and making toxicology studies quicker and more efficient.
Topics: Cells, Cultured; Drug Evaluation, Preclinical; Hepatocytes; High-Throughput Screening Assays; Humans; Inactivation, Metabolic
PubMed: 33142951
DOI: 10.3390/ijms21218182 -
Ageing Research Reviews Mar 2024Diseases of the central nervous system (CNS), including stroke, brain tumors, and neurodegenerative diseases, have a serious impact on human health worldwide, especially... (Review)
Review
Diseases of the central nervous system (CNS), including stroke, brain tumors, and neurodegenerative diseases, have a serious impact on human health worldwide, especially in elderly patients. The brain, which is one of the body's most metabolically dynamic organs, lacks fuel stores and therefore requires a continuous supply of energy substrates. Metabolic abnormalities are closely associated with the pathogenesis of CNS disorders. Post-translational modifications (PTMs) are essential regulatory mechanisms that affect the functions of almost all proteins. Succinylation, a broad-spectrum dynamic PTM, primarily occurs in mitochondria and plays a crucial regulatory role in various diseases. In addition to directly affecting various metabolic cycle pathways, succinylation serves as an efficient and rapid biological regulatory mechanism that establishes a connection between metabolism and proteins, thereby influencing cellular functions in CNS diseases. This review offers a comprehensive analysis of succinylation and its implications in the pathological mechanisms of CNS diseases. The objective is to outline novel strategies and targets for the prevention and treatment of CNS conditions.
Topics: Humans; Aged; Lysine; Proteins; Protein Processing, Post-Translational; Central Nervous System Diseases; Metabolic Networks and Pathways
PubMed: 38387517
DOI: 10.1016/j.arr.2024.102242 -
Cells Jul 2021Cancer stem cells (CSCs) are heterogeneous cells with stem cell-like properties that are responsible for therapeutic resistance, recurrence, and metastasis, and are the... (Review)
Review
Cancer stem cells (CSCs) are heterogeneous cells with stem cell-like properties that are responsible for therapeutic resistance, recurrence, and metastasis, and are the major cause for cancer treatment failure. Since CSCs have distinct metabolic characteristics that plays an important role in cancer development and progression, targeting metabolic pathways of CSCs appears to be a promising therapeutic approach for cancer treatment. Here we classify and discuss the unique metabolisms that CSCs rely on for energy production and survival, including mitochondrial respiration, glycolysis, glutaminolysis, and fatty acid metabolism. Because of metabolic plasticity, CSCs can switch between these metabolisms to acquire energy for tumor progression in different microenvironments compare to the rest of tumor bulk. Thus, we highlight the specific conditions and factors that promote or suppress CSCs properties to portray distinct metabolic phenotypes that attribute to CSCs in common cancers. Identification and characterization of the features in these metabolisms can offer new anticancer opportunities and improve the prognosis of cancer. However, the therapeutic window of metabolic inhibitors used alone or in combination may be rather narrow due to cytotoxicity to normal cells. In this review, we present current findings of potential targets in these four metabolic pathways for the development of more effective and alternative strategies to eradicate CSCs and treat cancer more effectively in the future.
Topics: Animals; Glutamine; Humans; Metabolic Networks and Pathways; Mitochondria; Molecular Targeted Therapy; Neoplastic Stem Cells; Oxidative Phosphorylation
PubMed: 34359941
DOI: 10.3390/cells10071772 -
Drug Metabolism Reviews Nov 2017Drug metabolism plays an important role in the drug disposal process. Differences in pharmacokinetics among individuals are the basis for personalized medicine. Natural... (Review)
Review
Drug metabolism plays an important role in the drug disposal process. Differences in pharmacokinetics among individuals are the basis for personalized medicine. Natural medicines, formed by long-term evolution of nature, prioritize the action of a target protein with a drug. Natural medicines are valued for structural diversity, low toxicity, low cost, and definite biological activities. Metabolic pathway and pharmacokinetic research of natural medicines is highly beneficial for clinical dose adjustment and the development of personalized medicine. This review was performed using a systematic search of all available literature. It provides an overview and discussion of metabolic pathways and the pharmacokinetics of natural medicines with low permeability. The related enzymes and factors affecting them are analyzed. The series of metabolic reactions, including phase I reactions(oxidation hydrolysis, and reduction reactions) and phase II reactions (binding reactions), catalyzed by intracellular metabolic enzymes (such as CYP450, esterase, SULT, and UGT enzymes) in tissues (such as liver and gastro-intestinal tract) or in the body fluid environment were examined. The administration route, drug dose, and delivery system had a large influence on absorption, metabolism, and pharmacokinetics. Natural medicines with low permeability had distinctive metabolisms and pharmacokinetics. The metabolic and in vivo kinetic properties were favorably modified by choosing suitable drug delivery systems, administration routes and drug doses, among other variables. This study provides valuable information for clinicians and pharmacists to guide patients safe, effective, and rational drug use. The research of metabolism and pharmacokinetics is significant in guiding personalized clinical medicine.
Topics: Animals; Biological Products; Biopharmaceutics; Humans; Metabolic Networks and Pathways; Permeability
PubMed: 28911247
DOI: 10.1080/03602532.2017.1377222 -
Toxins Sep 2020The determination of mycotoxins content in food is not sufficient for the prediction of their potential in vivo cytotoxicity because it does not reflect their... (Review)
Review
The determination of mycotoxins content in food is not sufficient for the prediction of their potential in vivo cytotoxicity because it does not reflect their bioavailability and mutual interactions within complex matrices, which may significantly alter the toxic effects. Moreover, many mycotoxins undergo biotransformation and metabolization during the intestinal absorption process. Biotransformation is predominantly the conversion of mycotoxins meditated by cytochrome P450 and other enzymes. This should transform the toxins to nontoxic metabolites but it may possibly result in unexpectedly high toxicity. Therefore, the verification of biotransformation and bioavailability provides valuable information to correctly interpret occurrence data and biomonitoring results. Among all of the methods available, the in vitro models using monolayer formed by epithelial cells from the human colon (Caco-2 cell) have been extensively used for evaluating the permeability, bioavailability, intestinal transport, and metabolism of toxic and biologically active compounds. Here, the strengths and limitations of both in vivo and in vitro techniques used to determine bioavailability are reviewed, along with current detailed data about biotransformation of mycotoxins. Furthermore, the molecular mechanism of mycotoxin effects is also discussed regarding the disorder of intestinal barrier integrity induced by mycotoxins.
Topics: Activation, Metabolic; Biological Availability; Caco-2 Cells; Epithelial Cells; Humans; Inactivation, Metabolic; Intestinal Absorption; Intestinal Mucosa; Mycotoxins; Permeability; Risk Assessment
PubMed: 33008111
DOI: 10.3390/toxins12100628