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Seminars in Radiation Oncology Jan 2019Since the recognition during the 20 century that cancer cells demonstrated fundamental alterations in the regulation of oxidative and glycolytic metabolism, many basic...
Since the recognition during the 20 century that cancer cells demonstrated fundamental alterations in the regulation of oxidative and glycolytic metabolism, many basic as well as translational scientists have proposed that targeting metabolic differences in cancer versus normal cells could be exploited to improve cancer therapy outcomes. With the recognition that dysregulation of mitochondrial redox metabolism leads to the increased steady-state levels of superoxide and hydrogen peroxide which could contribute to both aging and cancer; radiation biologists have pursued many avenues of targeting oxidative metabolic pathways to both selectively radiosensitive cancer cells as well as protect normal tissues during cancer therapy. Recent advances in exploiting redox metabolism for improving radiochemotherapy both from a basic and translational science point of view are the focus of the papers in this current issue of . The historical perspective underlying these areas of research as well as a unifying hypothesis for further advancing this research into clinical trials will be presented in this overview.
Topics: Antioxidants; Chemoradiotherapy; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Oxidation-Reduction; Oxidative Stress; Signal Transduction
PubMed: 30573179
DOI: 10.1016/j.semradonc.2018.10.010 -
Methods in Molecular Biology (Clifton,... 2021The complex enzyme kinetics displayed by drug-metabolizing cytochrome P450 enzymes (CYPs) (see Chapter 9 ) can, in part, be explained by an examination of their...
The complex enzyme kinetics displayed by drug-metabolizing cytochrome P450 enzymes (CYPs) (see Chapter 9 ) can, in part, be explained by an examination of their crystallographic protein structures. Fortunately, despite low sequence similarity between different families of drug-metabolizing CYPs, there exists a high degree of structural homology within the superfamily. This similarity in the protein fold allows for a direct comparison of the structural features of CYPs that contribute toward differences in substrate binding, heterotropic and homotropic cooperativity, and genetic variability in drug metabolism. In this chapter, we first provide an overview of the nomenclature and the role of structural features that are common in all CYPs. We then apply these definitions to understand the different substrate specificities and functions in the CYP3A, CYP2C, and CYP2D families of enzymes.
Topics: Crystallography, X-Ray; Cytochrome P-450 Enzyme System; Genetic Variation; Humans; Inactivation, Metabolic; Kinetics; Models, Molecular; Protein Folding; Protein Structure, Secondary; Substrate Specificity
PubMed: 34272695
DOI: 10.1007/978-1-0716-1554-6_7 -
Biochimica Et Biophysica Acta Sep 2016Two nuclear receptors, the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), participate in the xenobiotic detoxification system by regulating... (Review)
Review
Two nuclear receptors, the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), participate in the xenobiotic detoxification system by regulating the expression of drug-metabolizing enzymes and transporters in order to degrade and excrete foreign chemicals or endogenous metabolites. This review aims to expand the perceived relevance of PXR and CAR beyond their established role as master xenosensors to disease-oriented areas, emphasizing their modulation by small molecules. Structural studies of these receptors have provided much-needed insight into the nature of their binding promiscuity and the important elements that lead to ligand binding. Reports of species- and isoform-selective activation highlight the need for further scrutiny when extrapolating from animal data to humans, as animal models are at the forefront of early drug discovery. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.
Topics: Animals; Camptothecin; Constitutive Androstane Receptor; Coumestrol; Energy Metabolism; Gene Expression Regulation; Humans; Inactivation, Metabolic; Ketoconazole; Liver; Metformin; Pregnane X Receptor; Protein Binding; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Signal Transduction; Small Molecule Libraries; Species Specificity; Substrate Specificity
PubMed: 26921498
DOI: 10.1016/j.bbagrm.2016.02.013 -
Zhejiang Da Xue Xue Bao. Yi Xue Ban =... Feb 2021The metabolic reprogramming of tumor cells is characterized by increased uptake of various nutrients including glutamine. Glutamine metabolism provides the required... (Review)
Review
The metabolic reprogramming of tumor cells is characterized by increased uptake of various nutrients including glutamine. Glutamine metabolism provides the required substances for glycolysis and oxidative phosphorylation and affects the homeostasis of carbohydrate,fat and protein metabolism to induce the chemoresistance of tumor cells. Combination of chemotherapeutic agents with inhibitors specific to different components of glutamine metabolic pathway has obtained favorable clinical results on various tumors. Glutamine metabolic pathway plays a role in drug resistance of tumor cells in various ways. Firstly,the dynamic change of glutamine transporters can directly affect intracellular glutamine content thereby causing drug resistance; secondly,tumor stromal cells including adipocyte,fibroblast and metabolite from tumor microenvironment would give rise to immune-mediated drug resistance; thirdly,the expression and activity of key enzymes in glutamine metabolism also has a critical role in drug resistance of tumors. This article reviews the effects of glutamine metabolic pathway in the development of tumor chemoresistance,in terms of transporters,tumor microenvironment and metabolic enzymes,to provide insight for improving the therapeutic efficacy for drug-resistant tumors.
Topics: Cell Line, Tumor; Drug Resistance, Neoplasm; Glutamine; Glycolysis; Humans; Neoplasms; Oxidative Phosphorylation; Tumor Microenvironment
PubMed: 34117847
DOI: 10.3724/zdxbyxb-2021-0040 -
Drug Metabolism and Disposition: the... Dec 2023Drug-metabolizing enzymes and transporters (DMETs) are key regulators of the pharmacokinetics, efficacy, and toxicity of therapeutics. Over the past two decades,...
Drug-metabolizing enzymes and transporters (DMETs) are key regulators of the pharmacokinetics, efficacy, and toxicity of therapeutics. Over the past two decades, significant advancements in in vitro methodologies, targeted proteomics, in vitro to in vivo extrapolation methods, and integrated computational approaches such as physiologically based pharmacokinetic modeling have unequivocally contributed to improving our ability to quantitatively predict the role of DMETs in absorption, distribution, metabolism, and excretion and drug-drug interactions. However, the paucity of data regarding alterations in DMET activity in specific populations such as pregnant individuals, lactation, pediatrics, geriatrics, organ impairment, and disease states such as, cancer, kidney, and liver diseases and inflammation has restricted our ability to realize the full potential of these recent advancements. We envision that a series of carefully curated articles in a special supplementary issue of will summarize the latest progress in in silico, in vitro, and in vivo approaches to characterize alteration in DMET activity and quantitatively predict drug disposition in specific populations. In addition, the supplementary issue will underscore the current scientific knowledge gaps that present formidable barriers to fully understand the clinical implications of altered DMET activity in specific populations and highlight opportunities for multistakeholder collaboration to advance our collective understanding of this rapidly emerging area. SIGNIFICANCE STATEMENT: This commentary highlights current knowledge and identifies gaps and key challenges in understanding the role of drug-metabolizing enzymes and transporters (DMETs) in drug disposition in specific populations. With this commentary for the special issue in , the authors intend to increase interest and invite potential contributors whose research is focused or has aided in expanding the understanding around the role and impact of DMETs in drug disposition in specific populations.
Topics: Pregnancy; Female; Humans; Child; Membrane Transport Proteins; Liver Diseases; Drug Interactions; Inflammation; Metabolic Clearance Rate
PubMed: 37775331
DOI: 10.1124/dmd.123.001453 -
Drug Metabolism and Personalized Therapy Jun 2015Drug-metabolizing enzymes play a major role in the biotransformation and subsequent elimination of most drugs and xenobiotics from the body. Both phase I and phase II... (Review)
Review
Drug-metabolizing enzymes play a major role in the biotransformation and subsequent elimination of most drugs and xenobiotics from the body. Both phase I and phase II enzymes are highly polymorphic. Inter-individual differences in genes coding for drug-metabolizing enzymes are important for understanding variability in drug response and for individualization of drug prescription. The prevalence of genetic polymorphisms in drug metabolism varies widely with ethnicity, and marked differences in the distribution of allelic variants of genes encoding drug-metabolizing enzymes have been documented in populations of different racial origin. This review aimed to summarize the available studies on genetic polymorphisms associated with drug metabolism conducted in Italian populations and to compare the frequency of the various metabolizer phenotypes and most common variant alleles (and resulting genotypes) with corresponding values from other populations. Notably, published data are not extensive, and most studies were performed on relatively low numbers of individuals. In general, the frequency of polymorphisms in the cytochrome P450 (CYP) genes as well as in the investigated phase II enzymes in the Italian population was similar to values reported for other Caucasian populations. However, the prevalence of CYP2D6 gene duplication among Italians was found to be very high, confirming the higher frequency of CYP2D6 ultrarapid metabolizers in the Mediterranean area compared to Northern Europe. It is worth noting that a geographic gradient in the flavin-containing monooxygenase 3 polymorphism distribution was also seen, the Italian population showing higher similarity to other Mediterranean populations than to North Europeans.
Topics: Adult; Aged; Catechol O-Methyltransferase; Cytochrome P-450 Enzyme System; Genotype; Glucuronosyltransferase; Glutathione Transferase; Humans; Italy; Methyltransferases; Middle Aged; N-Terminal Acetyltransferases; Pharmaceutical Preparations; Polymorphism, Genetic; Sulfotransferases
PubMed: 25527811
DOI: 10.1515/dmdi-2014-0028 -
Frontiers in Pharmacology 2021Olanzapine, aripiprazole and risperidone are atypical antipsychotics or neuroleptics widely used for schizophrenia treatment. They induce various adverse drug reactions... (Review)
Review
Olanzapine, aripiprazole and risperidone are atypical antipsychotics or neuroleptics widely used for schizophrenia treatment. They induce various adverse drug reactions depending on their mechanisms of action: metabolic effects, such as weight gain and alterations of glucose and lipid metabolism; hyperprolactinemia and extrapyramidal effects, such as tremor, akathisia, dystonia, anxiety and distress. In this review, we listed polymorphisms associated with individual response variability to olanzapine, aripiprazole and risperidone. Olanzapine is mainly metabolized by cytochrome P450 enzymes, CYP1A2 and CYP2D6, whereas aripiprazole and risperidone metabolism is mainly mediated by CYP2D6 and CYP3A4. Polymorphisms in these genes and other enzymes and transporters, such as enzymes from the uridine 5'-diphospho-glucuronosyltransferase (UGT) family and ATP-binding cassette sub-family B member 1 (ABCB1), are associated to differences in pharmacokinetics. The three antipsychotics act on dopamine and serotonin receptors, among others, and several studies found associations between polymorphisms in these genes and variations in the incidence of adverse effects and in the response to the drug. Since olanzapine is metabolized by CYP1A2, a lower starting dose should be considered in patients treated with fluvoxamine or other CYP1A2 inhibitors. Regarding aripiprazole, a reduced dose should be administered in CYP2D6 poor metabolizers (PMs). Additionally, a reduction to a quarter of the normal dose is recommended if the patient is treated with concomitant CYP3A4 inhibitors. Risperidone dosage should be reduced for CYP2D6 PMs and titrated for CYPD6 ultrarapid metabolizers (UMs). Moreover, risperidone dose should be evaluated when a CYP2D6, CYP3A4 or ABCB1 inhibitor is administered concomitantly.
PubMed: 34335273
DOI: 10.3389/fphar.2021.711940 -
International Journal of Molecular... Jan 2022Enzymatic oxidations of thiophenes, including thiophene-containing drugs, are important for biodesulfurization of crude oil and drug metabolism of mono- and poly-cyclic... (Review)
Review
Enzymatic oxidations of thiophenes, including thiophene-containing drugs, are important for biodesulfurization of crude oil and drug metabolism of mono- and poly-cyclic thiophenes. Thiophene oxidative dearomatization pathways involve reactive metabolites, whose detection is important in the pharmaceutical industry, and are catalyzed by monooxygenase (sulfoxidation, epoxidation) and dioxygenase (sulfoxidation, dihydroxylation) enzymes. Sulfoxide and epoxide metabolites of thiophene substrates are often unstable, and, while -dihydrodiol metabolites are more stable, significant challenges are presented by both types of metabolite. Prediction of the structure, relative and absolute configuration, and enantiopurity of chiral metabolites obtained from thiophene enzymatic oxidation depends on the substrate, type of oxygenase selected, and molecular docking results. The racemization and dimerization of sulfoxides, / epimerization of dihydrodiol metabolites, and aromatization of epoxides are all factors associated with the mono- and di-oxygenase-catalyzed metabolism of thiophenes and thiophene-containing drugs and their applications in chemoenzymatic synthesis and medicine.
Topics: Biotransformation; Catalysis; Cytochrome P-450 Enzyme System; Dioxygenases; Inactivation, Metabolic; Metabolic Networks and Pathways; Mixed Function Oxygenases; Models, Molecular; Molecular Conformation; Molecular Structure; Oxidation-Reduction; Oxidative Stress; Protein Binding; Structure-Activity Relationship; Sulfoxides; Thiophenes
PubMed: 35055091
DOI: 10.3390/ijms23020909