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Environmental Health Perspectives Apr 1984The lung is a metabolically active organ that is engaged in secretion, clearance and other maintenance functions that require reducing potential, energy and substrates... (Review)
Review
The lung is a metabolically active organ that is engaged in secretion, clearance and other maintenance functions that require reducing potential, energy and substrates for biosynthesis. These metabolic requirements are met in part through uptake and catabolism of glucose which represents the major fuel utilized by lung tissues. Gluconeogenesis does not occur, and glycogen stores are limited so that the lung depends on the circulation for its glucose requirement. Other substrates can be metabolized by lung and contribute to the metabolic pool although their role has been less thoroughly studied. Glucose is catabolized in the lung by cytoplasmic and mitochondrial pathways that are responsive to regulatory mechanisms as in other tissues. Activity of the pentose cycle pathway of glucose catabolism is relatively high and generates the NADPH required for biosynthesis of lipid, detoxification reactions, and protection against oxidant stress. The ATP content of the lung is maintained by oxidative metabolism at levels comparable to other metabolically active organs. Alterations in lung intermediary metabolism may depress amine clearance, alter lung permeability, and influence the lung response to oxidant stress.
Topics: Adenosine Triphosphate; Animals; Biogenic Amines; Biological Transport, Active; Biotransformation; Cytoplasm; Energy Metabolism; Gluconeogenesis; Glucose; Glycolysis; Lung; Mitochondria; NAD; NADP; Oxygen; Oxygen Consumption; Pulmonary Edema; Rats
PubMed: 6376097
DOI: 10.1289/ehp.8455149 -
Drug Metabolism and Disposition: the... Aug 2015The recent symposium on "Target-Site" Drug Metabolism and Transport that was sponsored by the American Society for Pharmacology and Experimental Therapeutics at the 2014...
The recent symposium on "Target-Site" Drug Metabolism and Transport that was sponsored by the American Society for Pharmacology and Experimental Therapeutics at the 2014 Experimental Biology meeting in San Diego is summarized in this report. Emerging evidence has demonstrated that drug-metabolizing enzyme and transporter activity at the site of therapeutic action can affect the efficacy, safety, and metabolic properties of a given drug, with potential outcomes including altered dosing regimens, stricter exclusion criteria, or even the failure of a new chemical entity in clinical trials. Drug metabolism within the brain, for example, can contribute to metabolic activation of therapeutic drugs such as codeine as well as the elimination of potential neurotoxins in the brain. Similarly, the activity of oxidative and conjugative drug-metabolizing enzymes in the lung can have an effect on the efficacy of compounds such as resveratrol. In addition to metabolism, the active transport of compounds into or away from the site of action can also influence the outcome of a given therapeutic regimen or disease progression. For example, organic anion transporter 3 is involved in the initiation of pancreatic β-cell dysfunction and may have a role in how uremic toxins enter pancreatic β-cells and ultimately contribute to the pathogenesis of gestational diabetes. Finally, it is likely that a combination of target-specific metabolism and cellular internalization may have a significant role in determining the pharmacokinetics and efficacy of antibody-drug conjugates, a finding which has resulted in the development of a host of new analytical methods that are now used for characterizing the metabolism and disposition of antibody-drug conjugates. Taken together, the research summarized herein can provide for an increased understanding of potential barriers to drug efficacy and allow for a more rational approach for developing safe and effective therapeutics.
Topics: Animals; Biological Transport; Biological Transport, Active; Drug Delivery Systems; Humans; Inactivation, Metabolic; Pharmaceutical Preparations
PubMed: 25986849
DOI: 10.1124/dmd.115.064576 -
The Biochemical Journal Mar 2015Pyruvate is the end-product of glycolysis, a major substrate for oxidative metabolism, and a branching point for glucose, lactate, fatty acid and amino acid synthesis.... (Review)
Review
Pyruvate is the end-product of glycolysis, a major substrate for oxidative metabolism, and a branching point for glucose, lactate, fatty acid and amino acid synthesis. The mitochondrial enzymes that metabolize pyruvate are physically separated from cytosolic pyruvate pools and rely on a membrane transport system to shuttle pyruvate across the impermeable inner mitochondrial membrane (IMM). Despite long-standing acceptance that transport of pyruvate into the mitochondrial matrix by a carrier-mediated process is required for the bulk of its metabolism, it has taken almost 40 years to determine the molecular identity of an IMM pyruvate carrier. Our current understanding is that two proteins, mitochondrial pyruvate carriers MPC1 and MPC2, form a hetero-oligomeric complex in the IMM to facilitate pyruvate transport. This step is required for mitochondrial pyruvate oxidation and carboxylation-critical reactions in intermediary metabolism that are dysregulated in several common diseases. The identification of these transporter constituents opens the door to the identification of novel compounds that modulate MPC activity, with potential utility for treating diabetes, cardiovascular disease, cancer, neurodegenerative diseases, and other common causes of morbidity and mortality. The purpose of the present review is to detail the historical, current and future research investigations concerning mitochondrial pyruvate transport, and discuss the possible consequences of altered pyruvate transport in various metabolic tissues.
Topics: Animals; Biological Transport; Forecasting; Glycolysis; Humans; Membrane Transport Proteins; Metabolic Networks and Pathways; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Membranes; Monocarboxylic Acid Transporters; Pyruvic Acid
PubMed: 25748677
DOI: 10.1042/BJ20141171 -
Microbiology Spectrum Jun 2014Mycobacteria inhabit a wide range of intracellular and extracellular environments. Many of these environments are highly dynamic and therefore mycobacteria are faced... (Review)
Review
Mycobacteria inhabit a wide range of intracellular and extracellular environments. Many of these environments are highly dynamic and therefore mycobacteria are faced with the constant challenge of redirecting their metabolic activity to be commensurate with either replicative growth or a non-replicative quiescence. A fundamental feature in this adaptation is the ability of mycobacteria to respire, regenerate reducing equivalents and generate ATP via oxidative phosphorylation. Mycobacteria harbor multiple primary dehydrogenases to fuel the electron transport chain and two terminal respiratory oxidases, an aa3 -type cytochrome c oxidase and cytochrome bd-type menaquinol oxidase, are present for dioxygen reduction coupled to the generation of a protonmotive force. Hypoxia leads to the downregulation of key respiratory complexes, but the molecular mechanisms regulating this expression are unknown. Despite being obligate aerobes, mycobacteria have the ability to metabolize in the absence of oxygen and a number of reductases are present to facilitate the turnover of reducing equivalents under these conditions (e.g. nitrate reductase, succinate dehydrogenase/fumarate reductase). Hydrogenases and ferredoxins are also present in the genomes of mycobacteria suggesting the ability of these bacteria to adapt to an anaerobic-type of metabolism in the absence of oxygen. ATP synthesis by the membrane-bound F1FO-ATP synthase is essential for growing and non-growing mycobacteria and the enzyme is able to function over a wide range of protonmotive force values (aerobic to hypoxic). The discovery of lead compounds that target respiration and oxidative phosphorylation in Mycobacterium tuberculosis highlights the importance of this area for the generation of new front line drugs to combat tuberculosis.
Topics: Adenosine Triphosphate; Aerobiosis; Energy Metabolism; Metabolic Networks and Pathways; Mycobacterium tuberculosis; Oxidative Phosphorylation; Oxidoreductases
PubMed: 25346874
DOI: 10.1128/microbiolspec.MGM2-0015-2013 -
Journal of Applied Microbiology Jul 2015Ethanol production directly from CO2 , utilizing genetically engineered photosynthetic cyanobacteria as a biocatalyst, offers significant potential as a renewable and... (Review)
Review
Ethanol production directly from CO2 , utilizing genetically engineered photosynthetic cyanobacteria as a biocatalyst, offers significant potential as a renewable and sustainable source of biofuel. Despite the current absence of a commercially successful production system, significant resources have been deployed to realize this goal. Utilizing the pyruvate decarboxylase from Zymomonas species, metabolically derived pyruvate can be converted to ethanol. This review of both peer-reviewed and patent literature focuses on the genetic modifications utilized for metabolic engineering and the resultant effect on ethanol yield. Gene dosage, induced expression and cassette optimizat-ion have been analyzed to optimize production, with production rates of 0·1-0·5 g L(-1) day(-1) being achieved. The current 'toolbox' of molecular manipulations and future directions focusing on applicability, addressing the primary challenges facing commercialization of cyanobacterial technologies are discussed.
Topics: Autotrophic Processes; Biofuels; Cyanobacteria; Ethanol; Industrial Microbiology; Photosynthesis
PubMed: 25865951
DOI: 10.1111/jam.12821 -
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 -
Clinical Pharmacology and Therapeutics Sep 2013Metoprolol, a commonly prescribed β-blocker, is primarily metabolized by cytochrome P450 2D6 (CYP2D6), an enzyme with substantial genetic heterogeneity. Several smaller... (Meta-Analysis)
Meta-Analysis Review
Metoprolol, a commonly prescribed β-blocker, is primarily metabolized by cytochrome P450 2D6 (CYP2D6), an enzyme with substantial genetic heterogeneity. Several smaller studies have shown that metoprolol pharmacokinetics is influenced by CYP2D6 genotype and metabolizer phenotype. To increase robustness of metoprolol pharmacokinetic estimates, a systematic review and meta-analysis of pharmacokinetic studies that administered a single oral dose of immediate-release metoprolol were performed. Pooled analysis (n = 264) demonstrated differences in peak plasma metoprolol concentration, area under the concentration-time curve, elimination half-life, and apparent oral clearance that were 2.3-, 4.9-, 2.3-, and 5.9-fold between extensive and poor metabolizers, respectively, and 5.3-, 13-, 2.6-, and 15-fold between ultrarapid and poor metabolizers (all P < 0.001), respectively. Enantiomer-specific analysis revealed genotype-dependent enantio-selective metabolism, with nearly 40% greater R- than S-metoprolol metabolism in ultrarapid and extensive metabolizers. This study demonstrates a marked effect of CYP2D6 metabolizer phenotype on metoprolol pharmacokinetics and confirms enantiomer-specific metabolism of metoprolol.
Topics: Adrenergic beta-Antagonists; Cytochrome P-450 CYP2D6; Gene Dosage; Humans; Metoprolol; Phenotype; Stereoisomerism
PubMed: 23665868
DOI: 10.1038/clpt.2013.96 -
Cell Metabolism Jul 2017It has been appreciated for nearly 100 years that cancer cells are metabolically distinct from resting tissues. More recently understood is that this metabolic phenotype...
It has been appreciated for nearly 100 years that cancer cells are metabolically distinct from resting tissues. More recently understood is that this metabolic phenotype is not unique to cancer cells but instead reflects characteristics of proliferating cells. Similar metabolic transitions also occur in the immune system as cells transition from resting state to stimulated effectors. A key finding in immune metabolism is that the metabolic programs of different cell subsets are distinctly associated with immunological function. Further, interruption of those metabolic pathways can shift immune cell fate to modulate immunity. These studies have identified numerous metabolic similarities between cancer and immune cells but also critical differences that may be exploited and that affect treatment of cancer and immunological diseases.
Topics: Animals; Cell Proliferation; Glycolysis; Humans; Immunity; Immunity, Cellular; Inflammation; Metabolic Networks and Pathways; Neoplasms; Tumor Microenvironment
PubMed: 28683294
DOI: 10.1016/j.cmet.2017.06.004 -
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 -
Sheng Wu Gong Cheng Xue Bao = Chinese... Sep 2023As specialized intracellular parasite, viruses have no ability to metabolize independently, so they completely depend on the metabolic mechanism of host cells. Viruses... (Review)
Review
As specialized intracellular parasite, viruses have no ability to metabolize independently, so they completely depend on the metabolic mechanism of host cells. Viruses use the energy and precursors provided by the metabolic network of the host cells to drive their replication, assembly and release. Namely, viruses hijack the host cells metabolism to achieve their own replication and proliferation. In addition, viruses can also affect host cell metabolism by the expression of auxiliary metabolic genes (AMGs), affecting carbon, nitrogen, phosphorus, and sulfur cycles, and participate in microbial-driven biogeochemical cycling. This review summarizes the effect of viral infection on the host's core metabolic pathway from four aspects: cellular glucose metabolism, glutamine metabolism, fatty acid metabolism, and viral AMGs on host metabolism. It may facilitate in-depth understanding of virus-host interactions, and provide a theoretical basis for the treatment of viral diseases through metabolic intervention.
Topics: Humans; Metabolic Networks and Pathways; Virus Diseases; Carbohydrate Metabolism; Host Microbial Interactions; Lipid Metabolism
PubMed: 37805838
DOI: 10.13345/j.cjb.220888