-
Bioscience Reports Dec 2016Information about normal hepatic glucose metabolism may help to understand pathogenic mechanisms underlying obesity and diabetes mellitus. In addition, liver glucose... (Review)
Review
Information about normal hepatic glucose metabolism may help to understand pathogenic mechanisms underlying obesity and diabetes mellitus. In addition, liver glucose metabolism is involved in glycosylation reactions and connected with fatty acid metabolism. The liver receives dietary carbohydrates directly from the intestine via the portal vein. Glucokinase phosphorylates glucose to glucose 6-phosphate inside the hepatocyte, ensuring that an adequate flow of glucose enters the cell to be metabolized. Glucose 6-phosphate may proceed to several metabolic pathways. During the post-prandial period, most glucose 6-phosphate is used to synthesize glycogen via the formation of glucose 1-phosphate and UDP-glucose. Minor amounts of UDP-glucose are used to form UDP-glucuronate and UDP-galactose, which are donors of monosaccharide units used in glycosylation. A second pathway of glucose 6-phosphate metabolism is the formation of fructose 6-phosphate, which may either start the hexosamine pathway to produce UDP-N-acetylglucosamine or follow the glycolytic pathway to generate pyruvate and then acetyl-CoA. Acetyl-CoA may enter the tricarboxylic acid (TCA) cycle to be oxidized or may be exported to the cytosol to synthesize fatty acids, when excess glucose is present within the hepatocyte. Finally, glucose 6-phosphate may produce NADPH and ribose 5-phosphate through the pentose phosphate pathway. Glucose metabolism supplies intermediates for glycosylation, a post-translational modification of proteins and lipids that modulates their activity. Congenital deficiency of phosphoglucomutase (PGM)-1 and PGM-3 is associated with impaired glycosylation. In addition to metabolize carbohydrates, the liver produces glucose to be used by other tissues, from glycogen breakdown or from de novo synthesis using primarily lactate and alanine (gluconeogenesis).
Topics: Glucose; Glycosylation; Humans; Lipid Metabolism; Liver; Protein Processing, Post-Translational; Signal Transduction
PubMed: 27707936
DOI: 10.1042/BSR20160385 -
Signal Transduction and Targeted Therapy Feb 2021The arachidonic acid (AA) pathway plays a key role in cardiovascular biology, carcinogenesis, and many inflammatory diseases, such as asthma, arthritis, etc. Esterified... (Review)
Review
The arachidonic acid (AA) pathway plays a key role in cardiovascular biology, carcinogenesis, and many inflammatory diseases, such as asthma, arthritis, etc. Esterified AA on the inner surface of the cell membrane is hydrolyzed to its free form by phospholipase A2 (PLA2), which is in turn further metabolized by cyclooxygenases (COXs) and lipoxygenases (LOXs) and cytochrome P450 (CYP) enzymes to a spectrum of bioactive mediators that includes prostanoids, leukotrienes (LTs), epoxyeicosatrienoic acids (EETs), dihydroxyeicosatetraenoic acid (diHETEs), eicosatetraenoic acids (ETEs), and lipoxins (LXs). Many of the latter mediators are considered to be novel preventive and therapeutic targets for cardiovascular diseases (CVD), cancers, and inflammatory diseases. This review sets out to summarize the physiological and pathophysiological importance of the AA metabolizing pathways and outline the molecular mechanisms underlying the actions of AA related to its three main metabolic pathways in CVD and cancer progression will provide valuable insight for developing new therapeutic drugs for CVD and anti-cancer agents such as inhibitors of EETs or 2J2. Thus, we herein present a synopsis of AA metabolism in human health, cardiovascular and cancer biology, and the signaling pathways involved in these processes. To explore the role of the AA metabolism and potential therapies, we also introduce the current newly clinical studies targeting AA metabolisms in the different disease conditions.
Topics: Arachidonic Acids; Cell Membrane; Cytochrome P-450 Enzyme System; Humans; Leukotrienes; Lipid Metabolism; Lipoxins; Lipoxygenases; Metabolic Networks and Pathways; Phospholipases A2; Prostaglandin-Endoperoxide Synthases; Prostaglandins
PubMed: 33637672
DOI: 10.1038/s41392-020-00443-w -
Revue Medicale de Liege May 2019Ethanol is rapidly and almost completely absorbed by the digestive tract, mainly in the small intestine. Alcohol is then metabolized mainly in the liver where it is...
Ethanol is rapidly and almost completely absorbed by the digestive tract, mainly in the small intestine. Alcohol is then metabolized mainly in the liver where it is converted into acetaldehyde. Two systems contribute to this metabolization, the predominant alcohol dehydrogenase pathway, and the pathway controlled by the microsomal ethanol oxidizing system (MEOS), which is inducible and is also involved in the metabolism of other drugs. Acetaldehyde is then metabolized to acetate, which largely leaves the liver to be converted into acetyl-CoA in other tissues. Alcohol is oxidized preferentially to other energetic substrates, leading, in turn, to a decrease in oxidation of lipids which are stored in adipose tissue.
Topics: Acetaldehyde; Alcohol Dehydrogenase; Ethanol; Humans; Liver; Oxidation-Reduction
PubMed: 31206264
DOI: No ID Found -
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 -
IARC Scientific Publications 1980NDMA and NDEA are metabolized by a microsomal enzyme system that requires NADPH and oxygen. This metabolism leads to an unstable product which decomposes to yield a... (Review)
Review
NDMA and NDEA are metabolized by a microsomal enzyme system that requires NADPH and oxygen. This metabolism leads to an unstable product which decomposes to yield a reactive alkylating species. This species is too reactive chemically to influence significantly organs other than those in which it was generated. Alkylation of cellular components, particularly DNA, is a critical event in the initiation of tumours by these carcinogens. The greatest capacity to metabolize these nitrosamines to alkylating agents is found in the liver, but other organs, including the oesophagus, lung and kidney, are also capable of activation. These organs may be more susceptible to alkylation than the liver because they have a lesser ability to catalyse the removal of 06-alkylguanine from their DNA. However, orally administered doses of NDMA and the NDMA formed by nitrosation reactions within the gastrointestinal tract are rapidly absorbed from the upper part of the small intestine and carried to the liver in the portal blood supply. When small doses are given in this way, the capacity of the liver to metabolize the carcinogen is sufficient that the nitrosamine is effectively cleared in a 'first-pass' effect, leaving very little to interact with other organs. This has two important consequences: firstly, levels of NDMA found in peripheral blood may be significantly lower than those expected on the basis of total dietary exposure because of the rapid metabolism and effective clearance of the carcinogen by the liver; secondly, physiological factors leading to reduction of the metabolic activation in the liver may result in more of the carcinogen being metabolized other tissues and in a greater risk of cancer developing in those tissues.
Topics: Animals; Biotransformation; Carcinogens; DNA; Dimethylnitrosamine; Humans; Intestinal Absorption; Kidney; Kidney Neoplasms; Kinetics; Liver; Liver Neoplasms; Methylation; Methyltransferases; Oxygen Consumption; RNA
PubMed: 6160100
DOI: No ID Found -
Sports Medicine (Auckland, N.Z.) Mar 2017Substantial amounts of fructose are present in our diet. Unlike glucose, this hexose cannot be metabolized by most cells and has first to be converted into glucose,... (Review)
Review
Substantial amounts of fructose are present in our diet. Unlike glucose, this hexose cannot be metabolized by most cells and has first to be converted into glucose, lactate or fatty acids by enterocytes, hepatocytes and kidney proximal tubule cells, which all express specific fructose-metabolizing enzymes. This particular metabolism may then be detrimental in resting, sedentary subjects; however, this may also present some advantages for athletes. First, since fructose and glucose are absorbed through distinct, saturable gut transporters, co-ingestion of glucose and fructose may increase total carbohydrate absorption and oxidation. Second, fructose is largely metabolized into glucose and lactate, resulting in a net local lactate release from splanchnic organs (mostly the liver). This 'reverse Cori cycle' may be advantageous by providing lactate as an additional energy substrate to the working muscle. Following exercise, co-ingestion of glucose and fructose mutually enhance their own absorption and storage.
Topics: Athletes; Athletic Performance; Carbohydrate Metabolism; Dietary Carbohydrates; Exercise; Fructose; Glucose; Humans; Sports Nutritional Physiological Phenomena
PubMed: 28332117
DOI: 10.1007/s40279-017-0692-4 -
Microbes and Environments Mar 2017Anaerobic methane oxidation in archaea is often presented to operate via a pathway of "reverse methanogenesis". However, if the cumulative reactions of a methanogen are... (Review)
Review
Anaerobic methane oxidation in archaea is often presented to operate via a pathway of "reverse methanogenesis". However, if the cumulative reactions of a methanogen are run in reverse there is no apparent way to conserve energy. Recent findings suggest that chemiosmotic coupling enzymes known from their use in methylotrophic and acetoclastic methanogens-in addition to unique terminal reductases-biochemically facilitate energy conservation during complete CH oxidation to CO. The apparent enzyme modularity of these organisms highlights how microbes can arrange their energy metabolisms to accommodate diverse chemical potentials in various ecological niches, even in the extreme case of utilizing "reverse" thermodynamic potentials.
Topics: Anaerobiosis; Archaea; Energy Metabolism; Metabolic Networks and Pathways; Methane; Oxidation-Reduction
PubMed: 28321009
DOI: 10.1264/jsme2.ME16166 -
Progress in Molecular Biology and... 2012Xenobiotics have been defined as chemicals to which an organism is exposed that are extrinsic to the normal metabolism of that organism. Without metabolism, many... (Review)
Review
Xenobiotics have been defined as chemicals to which an organism is exposed that are extrinsic to the normal metabolism of that organism. Without metabolism, many xenobiotics would reach toxic concentrations. Most metabolic activity inside the cell requires energy, cofactors, and enzymes in order to occur. Xenobiotic-metabolizing enzymes can be divided into phase I, phase II, and transporter enzymes. Lipophilic xenobiotics are often first metabolized by phase I enzymes, which function to make xenobiotics more polar and provide sites for conjugation reactions. Phase II enzymes are conjugating enzymes and can directly interact with xenobiotics but more commonly interact with metabolites produced by phase I enzymes. Through both passive and active transport, these more polar metabolites are eliminated. Most xenobiotics are cleared through multiple enzymes and pathways. The relationship between chemical concentrations, enzyme affinity and quantity, and cofactor availability often determine which metabolic reactions dominate in a given individual.
Topics: Animals; Bacteria; Biological Transport; Environment; Humans; Inactivation, Metabolic; Mammals; Xenobiotics
PubMed: 22974737
DOI: 10.1016/B978-0-12-415813-9.00003-9 -
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 -
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