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Antioxidants & Redox Signaling Apr 2024Routine exposure to xenobiotics is unavoidable during our lifetimes. Certain xenobiotics are hazardous to human health, and are metabolized in the body to render them... (Review)
Review
Routine exposure to xenobiotics is unavoidable during our lifetimes. Certain xenobiotics are hazardous to human health, and are metabolized in the body to render them less toxic. During this process, several detoxification enzymes cooperatively metabolize xenobiotics. Glutathione (GSH) conjugation plays an important role in the metabolism of electrophilic xenobiotics. Recent advances in reactive sulfur and supersulfide (RSS) analyses showed that persulfides and polysulfides bound to low-molecular-weight thiols, such as GSH, and to protein thiols are abundant in both eukaryotes and prokaryotes. The highly nucleophilic nature of hydropersulfides and hydropolysulfides contributes to cell protection against oxidative stress and electrophilic stress. In contrast to GSH conjugation to electrophiles that is aided by glutathione -transferase (GST), persulfides and polysulfides can directly form conjugates with electrophiles without the catalytic actions of GST. The polysulfur bonds in the conjugates are further reduced by perthioanions and polythioanions derived from RSS to form sulfhydrated metabolites that are no longer electrophilic but rather nucleophilic, and differ from metabolites that are formed GSH conjugation. In view of the abundance of RSS in cells and tissues, metabolism of xenobiotics that is mediated by RSS warrants additional investigations, such as studies of the impact of microbiota-derived RSS on xenobiotic metabolism. Metabolites formed from reactions between electrophiles and RSS may be potential biomarkers for monitoring exposure to electrophiles and for studying their metabolism by RSS. 40, 679-690.
Topics: Humans; Xenobiotics; Sulfur; Oxidation-Reduction; Sulfhydryl Compounds; Sulfides
PubMed: 37294201
DOI: 10.1089/ars.2022.0172 -
European Journal of Drug Metabolism and... Oct 2017Genetic variability in drug-metabolizing enzymes and drug transporters is known to influence the pharmacokinetics of many drugs. Antimalarial drugs are a class of agents... (Review)
Review
Genetic variability in drug-metabolizing enzymes and drug transporters is known to influence the pharmacokinetics of many drugs. Antimalarial drugs are a class of agents known to utilize metabolic and elimination pathways prone to genetic variation. This paper aims to review the genetic variants affecting antimalarial medications and discuss their clinical implications. Data were identified for the genes coding for the cytochrome P450 (CYP) enzymes: CYP2C8, CYP2C19, CYP2A6, CYP2D6, CYP2B6, and the P-glycoprotein drug transporter. Adverse effects of amodiaquine were more common in patients with decreased CYP2C8 metabolism. CYP2C19 variants influenced the metabolism of proguanil but no differences in efficacy outcomes were observed. Ultra-metabolizers of CYP2A6 showed increased incidence of adverse effects of artesunate (prodrug for active metabolite, dihydroartemisinin). In the presence of efavirenz, mutations in CYP2B6 influenced the number of patients achieving day-7 lumefantrine concentrations above accepted therapeutic cut-offs. Lumefantrine concentrations were also influenced by ABCB1 variants in the presence of nevirapine. The most critical pharmacogenetic consideration identified was the association of glucose-6-phosphate dehydrogenase deficiency with development of hemolytic anemia and decreased hemoglobin levels in patients treated with primaquine or a combination of chlorproguanil-dapsone-artesunate. These findings demonstrate a need for close monitoring of patients originating from populations where genetic variation in metabolizing enzymes is prevalent, so as to ensure that optimal clinical outcomes are achieved. Future studies should determine which populations are at greatest risk of potential treatment failures and/or adverse effects, which drugs are most susceptible to genetic variation in metabolizing enzymes, and the impact of genetic influence on the efficacy and safety of first-line treatment regimens.
Topics: Animals; Antimalarials; Genetic Variation; Humans; Inactivation, Metabolic; Malaria; Membrane Transport Proteins; Pharmacogenetics
PubMed: 28070879
DOI: 10.1007/s13318-016-0399-1 -
Advances in Biological Regulation Jan 2020Blood platelets, produced by the fragmentation of megakaryocytes, play a key role in hemostasis and thrombosis. Being implicated in atherothrombosis and other... (Review)
Review
Blood platelets, produced by the fragmentation of megakaryocytes, play a key role in hemostasis and thrombosis. Being implicated in atherothrombosis and other thromboembolic disorders, they represent a major therapeutic target for antithrombotic drug development. Several recent studies have highlighted an important role for the lipid phosphatidylinositol 3 monophosphate (PtdIns3P) in megakaryocytes and platelets. PtdIns3P, present in small amounts in mammalian cells, is involved in the control of endocytic trafficking and autophagy. Its metabolism is finely regulated by specific kinases and phosphatases. Class II (α, β and γ) and III (Vps34) phosphoinositide-3-kinases (PI3Ks), INPP4 and Fig4 are involved in the production of PtdIns3P whereas PIKFyve, myotubularins (MTMs) and type II PIPK metabolize PtdIns3P. By regulating the turnover of different pools of PtdIns3P, class II (PI3KC2α) and class III (Vps34) PI3Ks have been recently involved in the regulation of platelet production and functions. These pools of PtdIns3P appear to modulate membrane organization and intracellular trafficking. Moreover, PIKFyve and INPP4 have been recently implicated in arterial thrombosis. In this review, we will discuss the role of PtdIns3P metabolizing enzymes in platelet production and function. Potential new anti-thrombotic therapeutic perspectives based on inhibitors targeting specifically PtdIns3P metabolizing enzymes will also be commented.
Topics: Animals; Blood Platelets; Humans; Phosphatidylinositol 3-Kinases; Phosphatidylinositol Phosphates; Protein Transport; Signal Transduction; Thrombopoiesis; Thrombosis
PubMed: 31604685
DOI: 10.1016/j.jbior.2019.100664 -
Journal of Biosciences Sep 2016Copper, although known as a micronutrient, has a pivotal role in modulating the cellular metabolism. Many studies have reported the role of copper in angiogenesis.... (Review)
Review
Copper, although known as a micronutrient, has a pivotal role in modulating the cellular metabolism. Many studies have reported the role of copper in angiogenesis. Copper chaperones are intracellular proteins that mediate copper trafficking to various cell organelles. However, the role and function of copper chaperones in relation to angiogenesis has to be further explored. The intracellular copper levels when in excess are deleterious and certain mutations of copper chaperones have been shown to induce cell death and influence various cellular metabolisms. The study of these chaperones will be helpful in understanding the players in the cascade of events in angiogenesis and their role in cellular metabolic pathways. In this review we have briefly listed the copper chaperones associated with angiogenic and metabolic signalling and their function.
Topics: Copper; Humans; Ion Transport; Metabolic Networks and Pathways; Molecular Chaperones; Neovascularization, Physiologic
PubMed: 27581939
DOI: 10.1007/s12038-016-9629-6 -
Anti-cancer Drugs Jan 2022Energetic pathways combine in the heart of metabolism. These essential routes supply energy for biochemical processes through glycolysis and oxidative phosphorylation....
Energetic pathways combine in the heart of metabolism. These essential routes supply energy for biochemical processes through glycolysis and oxidative phosphorylation. Moreover, they support the synthesis of various biomolecules employed in growth and survival over branching pathways. Yet, cellular energetics are often misguided in cancers as a result of the mutations and altered signaling. As nontransformed and Pasteur-like cells metabolize glucose through oxidative respiration when only oxygen is sufficient, some cancer cells bypass this metabolic switch and run glycolysis at higher rates even in the presence of oxygen. The phenomenon is called aerobic glycolysis or the Warburg effect. An increasing number of studies indicate that both Warburg and Pasteur phenotypes are recognized in the cancer microenvironment and take vital roles in the regulation of drug resistance mechanisms such as redox homeostasis, apoptosis and autophagy. Therefore, the different phenotypes call for different therapeutic approaches. Combined therapies targeting energy metabolism grant new opportunities to overcome the challenges. Nevertheless, new biomarkers emerge to classify the energetic subtypes, thereby the cancer therapy, as our knowledge in coupling energy metabolism with cancer behavior grows.
Topics: Antineoplastic Agents; Apoptosis; Autophagy; Biomarkers; Drug Resistance, Neoplasm; Energy Metabolism; Glycolysis; Humans; Neoplasms; Oxidative Phosphorylation; Phenotype; Warburg Effect, Oncologic
PubMed: 34538862
DOI: 10.1097/CAD.0000000000001236 -
Scientific Reports Feb 2020Dietary intake in early lactating cows is outmatched by milk production. These cows experience a negative energy balance, resulting in a distinct blood metabolism and...
Dietary intake in early lactating cows is outmatched by milk production. These cows experience a negative energy balance, resulting in a distinct blood metabolism and poor reproductive function due to impaired ovulation and increased embryo loss. We hypothesize that oocytes from lactating cows undergoing transient metabolic stress exhibit a different epigenetic profile crucial for developmental competence. To investigate this, we collected oocytes from metabolically-profiled cows at early- and mid-postpartum stages and characterized their epigenetic landscape compared with control heifers using whole-genome bisulfite sequencing. Early-postpartum cows were metabolically deficient with a significantly lower energy balance and significantly higher concentrations of non-esterified fatty acids and beta-hydroxybutyrate than mid-postpartum animals and control heifers. Accordingly, 32,990 early-postpartum-specific differentially methylated regions (DMRs) were found in genes involved in metabolic pathways, carbon metabolism, and fatty acid metabolism, likely descriptive of the epigenetic regulation of metabolism in early-postpartum oocytes. DMRs found overlapping CpG islands and exons of imprinted genes such as MEST and GNAS in early-postpartum oocytes suggest that early lactation metabolic stress may affect imprint acquisition, which could explain the embryo loss. This whole-genome approach introduces potential candidate genes governing the link between metabolic stress and the reproductive outcome of oocytes.
Topics: Animals; Cattle; CpG Islands; DNA Methylation; Epigenesis, Genetic; Female; Gene Expression Regulation; Genome; Lactation; Metabolome; Oocytes; Postpartum Period
PubMed: 32047242
DOI: 10.1038/s41598-020-59410-8 -
Scientific Reports Dec 2021Trade-offs are inherent to biochemical networks governing diverse cellular functions, from gene expression to metabolism. Yet, trade-offs between fluxes of biochemical...
Trade-offs are inherent to biochemical networks governing diverse cellular functions, from gene expression to metabolism. Yet, trade-offs between fluxes of biochemical reactions in a metabolic network have not been formally studied. Here, we introduce the concept of absolute flux trade-offs and devise a constraint-based approach, termed FluTO, to identify and enumerate flux trade-offs in a given genome-scale metabolic network. By employing the metabolic networks of Escherichia coli and Saccharomyces cerevisiae, we demonstrate that the flux trade-offs are specific to carbon sources provided but that reactions involved in the cofactor and prosthetic group biosynthesis are present in trade-offs across all carbon sources supporting growth. We also show that absolute flux trade-offs depend on the biomass reaction used to model the growth of Arabidopsis thaliana under different carbon and nitrogen conditions. The identified flux trade-offs reflect the tight coupling between nitrogen, carbon, and sulphur metabolisms in leaves of C plants. Altogether, FluTO provides the means to explore the space of alternative metabolic routes reflecting the constraints imposed by inherent flux trade-offs in large-scale metabolic networks.
Topics: Algorithms; Arabidopsis; Carbon; Computational Biology; Energy Metabolism; Escherichia coli; Metabolic Networks and Pathways; Models, Biological; Nutrients; Saccharomyces cerevisiae; Systems Biology
PubMed: 34893666
DOI: 10.1038/s41598-021-03224-9 -
ACS Applied Materials & Interfaces Feb 2024Tumor development and metastasis are closely related to the complexity of the metabolism network. Recently, metabolism reprogramming strategies have attracted much... (Review)
Review
Tumor development and metastasis are closely related to the complexity of the metabolism network. Recently, metabolism reprogramming strategies have attracted much attention in tumor metabolism therapy. Although there is preliminary success of metabolism therapy agents, their therapeutic effects have been restricted by the effective reaching of the tumor sites of drugs. Nanodelivery systems with unique physical properties and elaborate designs can specifically deliver to the tumors. In this review, we first summarize the research progress of nanodelivery systems based on tumor metabolism reprogramming strategies to enhance therapies by depleting glucose, inhibiting glycolysis, depleting lactic acid, inhibiting lipid metabolism, depleting glutamine and glutathione, and disrupting metal metabolisms combined with other therapies, including chemotherapy, radiotherapy, photodynamic therapy, etc. We further discuss in detail the advantages of nanodelivery systems based on tumor metabolism reprogramming strategies for tumor therapy. As well as the opportunities and challenges for integrating nanodelivery systems into tumor metabolism therapy, we analyze the outlook for these emerging areas. This review is expected to improve our understanding of modulating tumor metabolisms for enhanced therapy.
Topics: Humans; Metabolic Reprogramming; Glycolysis; Neoplasms; Lipid Metabolism; Tumor Microenvironment
PubMed: 38302434
DOI: 10.1021/acsami.3c15686 -
European Journal of Drug Metabolism and... Apr 2016Amino-noscapine is a promising noscapine derivative undergoing R&D as an efficient anti-tumor drug. In vitro phase I metabolism incubation system was employed. In vitro...
Amino-noscapine is a promising noscapine derivative undergoing R&D as an efficient anti-tumor drug. In vitro phase I metabolism incubation system was employed. In vitro samples were analyzed using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry. In vitro recombinant CYP isoforms screening was used to identify the drug-metabolizing enzymes involved in the metabolism of amino-noscapine. Multiple metabolics were formed, including the formation of metabolite undergoing cleavage of methylenedioxy group, hydroxylated metabolites, demethylated metabolites, and metabolites undergoing C-C cleavage. Nearly, all the CYP isoforms were involved in the metabolism of metabolites II, III, VII, IX, and X. CYP1A1 was demonstrated to be the major CYP isoform for the formation of metabolites IV and V. CYP1A1 and CYP3A4 mainly catalyzed the formation of metabolite VI. The metabolic formation of VIII was mainly catalyzed by CYP2C19 and CYP3A4. CYP3A4 was the main enzyme for the formation of XI. CYP2C9 mainly catalyzed the generation of metabolite XII. In conclusion, the metabolic pathway of amino-noscapine was elucidated in the present study using in vitro phase I incubation experiment, including the structural elucidation of metabolites and involved phase I drug-metabolizing enzymes. This information was helpful for the R&D of amino-noscapine.
Topics: Chromatography, High Pressure Liquid; Cytochrome P-450 Enzyme System; Humans; Metabolic Detoxication, Phase I; Microsomes, Liver; Noscapine; Spectrometry, Mass, Electrospray Ionization
PubMed: 25527252
DOI: 10.1007/s13318-014-0241-6 -
Drug Metabolism Reviews Aug 2014Aliphatic nitrogen heterocycles such as piperazine, piperidine, pyrrolidine, morpholine, aziridine, azetidine, and azepane are well known building blocks in drug design... (Review)
Review
Aliphatic nitrogen heterocycles such as piperazine, piperidine, pyrrolidine, morpholine, aziridine, azetidine, and azepane are well known building blocks in drug design and important core structures in approved drug therapies. These core units have been targets for metabolic attack by P450s and other drug metabolizing enzymes such as aldehyde oxidase and monoamine oxidase (MAOs). The electron rich nitrogen and/or α-carbons are often major sites of metabolism of alicyclic amines. The most common biotransformations include N-oxidation, N-conjugation, oxidative N-dealkylation, ring oxidation, and ring opening. In some instances, the metabolic pathways generate electrophilic reactive intermediates and cause bioactivation. However, potential bioactivation related adverse events can be attenuated by structural modifications. Hence it is important to understand the biotransformation pathways to design stable drug candidates that are devoid of metabolic liabilities early in the discovery stage. The current review provides a comprehensive summary of biotransformation and bioactivation pathways of aliphatic nitrogen containing heterocycles and strategies to mitigate metabolic liabilities.
Topics: Amines; Animals; Biotransformation; Cytochrome P-450 Enzyme System; Humans; Inactivation, Metabolic; Pharmaceutical Preparations
PubMed: 24909234
DOI: 10.3109/03602532.2014.924962