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Yakugaku Zasshi : Journal of the... 2017Since more than 70% of clinically used drugs are excreted from the body through metabolic processes, drug metabolism is a key determinant of pharmacokinetics, drug... (Review)
Review
Since more than 70% of clinically used drugs are excreted from the body through metabolic processes, drug metabolism is a key determinant of pharmacokinetics, drug response and drug toxicity. Much progress has been made in understanding drug-drug interactions via the inhibition or induction of cytochrome P450s (P450, CYP), as well as the effects of genetic polymorphisms of P450s on pharmacokinetics, and this has facilitated the progress of optimized pharmacotherapy in the clinic. Now, similar information is needed for non-CYP enzymes, especially concerning Phase I enzymes, based on advanced basic and clinical studies. Recently, it was revealed that post-transcriptional regulation by microRNAs or RNA editing plays a significant role in regulating the expression of drug-metabolizing enzymes, thus conferring variability in the detoxification and metabolic activation of drugs or chemicals. Changes in the expression profile of microRNAs in tissues or body fluids can be a biomarker of drug response and toxicity; therefore, such studies could also be useful for drug repositioning. In addition, microRNAs are involved in pharmacogenetics, because single nucleotide polymorphisms in microRNA binding sites of mRNAs, or microRNAs themselves, may cause changes in gene expression. Some microRNA-related polymorphisms could be biomarkers of the clinical outcome of pharmacotherapy. In this review article, recent progress and future directions for drug metabolism studies are discussed.
Topics: Binding Sites; Cytochrome P-450 Enzyme System; Drug Interactions; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Humans; Inactivation, Metabolic; MicroRNAs; Pharmaceutical Preparations; Pharmacogenetics; Pharmacokinetics; Polymorphism, Genetic; Polymorphism, Single Nucleotide; RNA Editing; RNA Processing, Post-Transcriptional
PubMed: 28566576
DOI: 10.1248/yakushi.16-00250-5 -
Communications Biology Feb 2021Caenorhabditis elegans is an instrumental research model used to advance our knowledge in areas including development, metabolism, and aging. However, research on... (Comparative Study)
Comparative Study
Caenorhabditis elegans is an instrumental research model used to advance our knowledge in areas including development, metabolism, and aging. However, research on metabolism and/or other measures of health/aging are confounded by the nematode's food source in the lab, live E. coli bacteria. Commonly used treatments, including ultraviolet irradiation and antibiotics, are successful in preventing bacterial replication, but the bacteria can remain metabolically active. The purpose of this study is to develop a metabolically inactive food source for the worms that will allow us to minimize the confounding effects of bacterial metabolism on worm metabolism and aging. Our strategy is to use a paraformaldehyde (PFA) treated E. coli food source and to determine its effects on worm health, metabolism and longevity. We initially determine the lowest possible concentrations of PFA necessary to rapidly and reproducibly kill bacteria. We then measure various aspects of worm behavior, healthspan and longevity, including growth rate, food attraction, brood size, lifespan and metabolic assessments, such as oxygen consumption and metabolomics. Our resulting data show that worms eat and grow well on these bacteria and support the use of 0.5% PFA-killed bacteria as a nematode food source for metabolic, drug, and longevity experiments.
Topics: Animal Feed; Animals; Caenorhabditis elegans; Energy Metabolism; Escherichia coli; Feeding Behavior; Fertility; Formaldehyde; Longevity; Metabolome; Metabolomics; Microbial Viability; Nutritive Value; Polymers; Time Factors
PubMed: 33637830
DOI: 10.1038/s42003-021-01764-4 -
Advances in Cancer Research 2019Fundamental metabolic pathways are essential for mammalian cells to provide energy, precursors for biosynthesis of macromolecules, and reducing power for redox... (Review)
Review
Fundamental metabolic pathways are essential for mammalian cells to provide energy, precursors for biosynthesis of macromolecules, and reducing power for redox regulation. While dysregulated metabolism (e.g., aerobic glycolysis also known as the Warburg effect) has long been recognized as a hallmark of cancer, recent discoveries of metabolic reprogramming in immune cells during their activation and differentiation have led to an emerging concept of "immunometabolism." Considering the recent success of cancer immunotherapy in the treatment of several cancer types, increasing research efforts are being made to elucidate alterations in metabolic profiles of cancer and immune cells during their interplays in the setting of cancer progression and immunotherapy. In this review, we summarize recent advances in studies of metabolic reprogramming in cancer as well as differentiation and functionality of various immune cells. In particular, we will elaborate how distinct metabolic pathways in the tumor microenvironment cause functional impairment of immune cells and contribute to immune evasion by cancer. Lastly, we highlight the potential of metabolically reprogramming the tumor microenvironment to promote effective and long-lasting antitumor immunity for improved immunotherapeutic outcomes.
Topics: Animals; Antineoplastic Agents; Cellular Reprogramming; Energy Metabolism; Glycolysis; Humans; Immune System; Immunotherapy; Metabolome; Neoplasms; Signal Transduction; T-Lymphocytes; Tumor Microenvironment
PubMed: 31202359
DOI: 10.1016/bs.acr.2019.03.004 -
Biochemical Pharmacology Apr 2012Chemotherapy is one of the three most common treatment modalities for cancer. However, its efficacy is limited by multidrug resistant cancer cells. Drug metabolizing... (Review)
Review
Chemotherapy is one of the three most common treatment modalities for cancer. However, its efficacy is limited by multidrug resistant cancer cells. Drug metabolizing enzymes (DMEs) and efflux transporters promote the metabolism, elimination, and detoxification of chemotherapeutic agents. Consequently, elevated levels of DMEs and efflux transporters reduce the therapeutic effectiveness of chemotherapeutics and, often, lead to treatment failure. Nuclear receptors, especially pregnane X receptor (PXR, NR1I2) and constitutive androstane activated receptor (CAR, NR1I3), are increasingly recognized for their role in xenobiotic metabolism and clearance as well as their role in the development of multidrug resistance (MDR) during chemotherapy. Promiscuous xenobiotic receptors, including PXR and CAR, govern the inducible expressions of a broad spectrum of target genes that encode phase I DMEs, phase II DMEs, and efflux transporters. Recent studies conducted by a number of groups, including ours, have revealed that PXR and CAR play pivotal roles in the development of MDR in various human carcinomas, including prostate, colon, ovarian, and esophageal squamous cell carcinomas. Accordingly, PXR/CAR expression levels and/or activation statuses may predict prognosis and identify the risk of drug resistance in patients subjected to chemotherapy. Further, PXR/CAR antagonists, when used in combination with existing chemotherapeutics that activate PXR/CAR, are feasible and promising options that could be utilized to overcome or, at least, attenuate MDR in cancer cells.
Topics: Constitutive Androstane Receptor; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Enzymes; Humans; Inactivation, Metabolic; Neoplasms; Pregnane X Receptor; Receptors, Aryl Hydrocarbon; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid
PubMed: 22326308
DOI: 10.1016/j.bcp.2012.01.030 -
Journal of Genetics Mar 2017In the present scenario of increased accumulation of pesticides in the environment, it is important to understand its impact on human health. The focus is on... (Review)
Review
In the present scenario of increased accumulation of pesticides in the environment, it is important to understand its impact on human health. The focus is on gene-environment interaction, highlighting the consequences and factors that may halt the biotransformation of some pesticides and change their actual dose response curve due to mixed exposure to pesticides. The paraoxonase and cytochrome P450 gene families are involved in the metabolism of oxon derivate (toxic than its parent compound) of organophosphate pesticides, thus, mutations in these genes may impact the metabolic outcome of pesticides and subsequent health hazards. The complex multi gene-environment interaction and one gene - one risk factor are two different aspects to understand the potential health effect related to environmental exposure studies. The genetic polymorphisms are associated with varying levels of risk within the population, as gene products of varied genotype alter the biotransformation of exogenous/endogenous substrates. This paper is aimed to review the impact of endogenous and exogenous factors on a mechanistic pathway of organophosphate pesticide biotransformation and various risk associated with it among the human population. Understanding the genetic polymorphism of genes involved in pesticide metabolism and highlighting the gene isoform dependent interindividual differences to metabolize particular pesticides may help us to unravel the reasons behind differential toxicity for pesticides exposure than expected.
Topics: Animals; Aryldialkylphosphatase; Biotransformation; Cytochrome P-450 Enzyme System; Drug Resistance; Gene Expression Regulation; Gene-Environment Interaction; Genetic Predisposition to Disease; Genetic Variation; Humans; Metabolic Networks and Pathways; Organophosphorus Compounds; Pesticides; Pharmacogenetics; Polymorphism, Genetic; Signal Transduction
PubMed: 28360405
DOI: 10.1007/s12041-017-0741-7 -
Human Cell Jul 2023Metabolic and inflammatory pathways are highly interdependent, and both systems are dysregulated in Type 2 diabetes (T2D). T2D is associated with pre-activated... (Review)
Review
Metabolic and inflammatory pathways are highly interdependent, and both systems are dysregulated in Type 2 diabetes (T2D). T2D is associated with pre-activated inflammatory signaling networks, aberrant cytokine production and increased acute phase reactants which leads to a pro-inflammatory 'feed forward loop'. Nutrient 'excess' conditions in T2D with hyperglycemia, elevated lipids and branched-chain amino acids significantly alter the functions of immune cells including neutrophils. Neutrophils are metabolically active cells and utilizes energy from glycolysis, stored glycogen and β-oxidation while depending on the pentose phosphate pathway for NADPH for performing effector functions such as chemotaxis, phagocytosis and forming extracellular traps. Metabolic changes in T2D result in constitutive activation and impeded acquisition of effector or regulatory activities of neutrophils and render T2D subjects for recurrent infections. Increased flux through the polyol and hexosamine pathways, elevated production of advanced glycation end products (AGEs), and activation of protein kinase C isoforms lead to (a) an enhancement in superoxide generation; (b) the stimulation of inflammatory pathways and subsequently to (c) abnormal host responses. Neutrophil dysfunction diminishes the effectiveness of wound healing, successful tissue regeneration and immune surveillance against offending pathogens. Hence, Metabolic reprogramming in neutrophils determines frequency, severity and duration of infections in T2D. The present review discusses the influence of the altered immuno-metabolic axis on neutrophil dysfunction along with challenges and therapeutic opportunities for clinical management of T2D-associated infections.
Topics: Humans; Neutrophils; Diabetes Mellitus, Type 2; Glycolysis; Hyperglycemia; Oxidation-Reduction
PubMed: 37115481
DOI: 10.1007/s13577-023-00905-7 -
Current Issues in Molecular Biology 2014Although the liver has long been considered as a main organ responsible for drug metabolism, the role of the gut metabolizing enzymes and the gut microflora is becoming... (Review)
Review
Although the liver has long been considered as a main organ responsible for drug metabolism, the role of the gut metabolizing enzymes and the gut microflora is becoming more profoundly evident in drug metabolism, absorption and overall efficacy. This review will explore various mechanisms by which the gut-microflora influences drug pharmacokinetics including biotransformation, bioactivation, and biodegradation as well as up- or down-regulation of the epithelial transporters. The gut-luminal fluids, intestinal mucosa and gut microflora contain high concentrations of various enzymes which are responsible for the oxidation, hydrolysis and conjugation of drugs. Such metabolic reactions may lead to either drug over- or under-dosing, which impacts the drugs efficacy and safety. The processes, by which the intestinal enzymes and gut-protein transporters influence drug pharmacokinetic parameters, will be detailed. Since the intestinal microflora plays an important role in physiological, nutritional, metabolic, and immunological processes in human body, there is currently some interest in the manipulation of its composition and activity by administering probiotics. This review will also examine the capacity of probiotics to interact with resident microbial community, affecting the respective enzymes or by providing their own specific enzymatic activities that may consequently change the bioavailability and pharmacological activity of concomitantly taken drugs.
Topics: Administration, Oral; Biological Availability; Biotransformation; Gastrointestinal Microbiome; Humans; Intestinal Mucosa; Intestines; Liver; Prescription Drugs; Probiotics
PubMed: 24002548
DOI: No ID Found -
Yakugaku Zasshi : Journal of the... 2019Human hepatocytes possess a wider range of phase I and II drug-metabolizing enzyme activities than other liver tissue-derived products, such as human liver microsomes.... (Review)
Review
Human hepatocytes possess a wider range of phase I and II drug-metabolizing enzyme activities than other liver tissue-derived products, such as human liver microsomes. Thus, hepatocytes may be useful for predicting the in vivo metabolic fate of new drugs of abuse in humans. Recently, new types of human hepatocytes have been made commercially available for use in drug metabolism studies, such as a liver tumor-derived cell line (HepaRG), and a human induced pluripotent stem cell-derived hepatocyte (h-iPS-HEP). In our laboratory, HepaRG has been used to elucidate the metabolic pathways of XLR-11, a synthetic cannabinoid, and its thermal degradant. In addition, the potential of h-iPS-HEP to metabolize drugs was assessed using fentanyl as a model drug, and indeed, h-iPS-HEP exhibited a pattern for fentanyl metabolite formation similar to that observed in vivo. In addition, the phase I and II drug-metabolizing enzyme activities of HepaRG, h-iPS-HEP, liver-humanized mouse-derived hepatocytes (PXB-cellsTM), and human primary hepatocytes were evaluated and compared. HepaRG showed high phase I and II drug metabolism activities; however, the CYP2D6 activity in these cells was quite low, and therefore h-iPS-HEP lacked O-methylation and conjugation activities. PXB-cells provided optimal results, i.e., these cells are extremely easy to use, and they possess higher phase I and II drug-metabolizing enzyme activities than the other cells tested. Although PXB-cells are contaminated with mouse-derived cells up to a concentration of several percent, this cell system appears to be promising for the prediction of in vivo human metabolism of new drugs of abuse.
Topics: Animals; Cannabinoids; Cell Line; Cytochrome P-450 CYP2D6; Fentanyl; Hepatocytes; Humans; Methylation; Mice; Substance-Related Disorders
PubMed: 31061338
DOI: 10.1248/yakushi.18-00166-3 -
The AAPS Journal Jun 2009The bioavailability of drugs from oral formulations is influenced by many physiological factors including gastrointestinal fluid composition, pH and dynamics, transit... (Review)
Review
The bioavailability of drugs from oral formulations is influenced by many physiological factors including gastrointestinal fluid composition, pH and dynamics, transit and motility, and metabolism and transport, each of which may vary with age, gender, race, food, and disease. Therefore, oral bioavailability, particularly of poorly soluble and/or poorly permeable compounds and those that are extensively metabolized, often exhibits a high degree of inter- and intra-individual variability. While several models and algorithms have been developed to predict bioavailability in an average person, efforts to accommodate intrinsic variability in the component processes are less common. An approach that incorporates such variability for human populations within a mechanistic framework is described together with examples of its application to drug and formulation development.
Topics: Animals; Biological Availability; Biotransformation; Chemistry, Pharmaceutical; Forecasting; Humans; Intestinal Absorption; Pharmaceutical Preparations; Pharmacokinetics; Population; Solubility
PubMed: 19381840
DOI: 10.1208/s12248-009-9099-y -
International Journal of Molecular... Mar 2021Progress in understanding the mechanisms of the idiosyncratic drug induced liver injury (iDILI) was highlighted in a scientometric investigation on the knowledge mapping... (Review)
Review
Progress in understanding the mechanisms of the idiosyncratic drug induced liver injury (iDILI) was highlighted in a scientometric investigation on the knowledge mapping of iDILI throughout the world, but uncertainty remained on metabolic risk factors of iDILI, the focus of the present review article. For the first time, a quantitative analysis of 3312 cases of iDILI assessed for causality with RUCAM (Roussel Uclaf Causality Assessment Method) showed that most drugs (61.1%) were metabolized by cytochrome P450 (CYP) isoforms: 49.6% by CYP 3A4/5, 24.6% by CYP 2C9, 13.2% by CYP 2E1, 7.3% by CYP 2C19, 3.5% by CYP 1A2 and 1.8% by CYP 2D6. Other studies showed high OR (odds ratio) for drugs metabolized by unspecified CYPs but the iDILI cases were not assessed for causality with RUCAM, a major shortcoming. In addition to critical comments on methodological flaws, several risk factors of iDILI were identified such as high but yet recommended daily drug doses, actual daily drug doses taken by the patients, hepatic drug metabolism and drug lipophilicity. These risk factors are subject to controversies by many experts seen critically also by others who outlined that none of these medication characteristics is able to predict iDILI with high confidence, leading to the statement of an outstanding caveat. It was also argued that all previous studies lacked comprehensive data because the number of examined drugs was relatively small as compared to the number of approved new molecular entities or currently used oral prescription drugs. In conclusion, trends are evident that some metabolic parameters are likely risk factors of iDILI but strong evidence can only be achieved when methodological issues will be successfully met.
Topics: Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme System; Humans; Inactivation, Metabolic; Lipids; Liver; Metabolic Clearance Rate; Protein Isoforms; Reactive Oxygen Species; Risk Factors; Technology, Pharmaceutical
PubMed: 33810530
DOI: 10.3390/ijms22073441