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The British Journal of Nutrition Mar 1984Volatile fatty acids (VFA) absorption in the large intestine of the anaesthetized rabbit was evaluated by measuring variations in the concentration of VFA in intestinal...
Volatile fatty acids (VFA) absorption in the large intestine of the anaesthetized rabbit was evaluated by measuring variations in the concentration of VFA in intestinal loops and plasma arteriovenous differences. Metabolic conversions were studied using [1-14C]acetate, [1-14C]propionate and [3,4-14C]butyrate. The hind-gut tissues metabolized the three VFA, although this metabolism varied with the segment studied. Butyrate was the best respiratory fuel for the colonic wall, followed by propionate; acetate participated also, but it was mainly converted to glutamate. The liver was the main organ metabolizing absorbed propionate and butyrate; acetate was available for extrahepatic tissue metabolism. For the rabbit, VFA represented about 40% of the maintenance energy requirement.
Topics: Acetates; Animals; Blood Glucose; Butyrates; Butyric Acid; Energy Metabolism; Fatty Acids, Volatile; Intestinal Absorption; Intestine, Large; Ketone Bodies; Lactates; Liver; Male; Propionates; Rabbits
PubMed: 6704374
DOI: 10.1079/bjn19840031 -
Environmental Health Perspectives Dec 1979There are five possible processes of intestinal absorption of xenobiotics. These are active transport, passive diffusions, pinocytosis, filtration through "pores," and...
There are five possible processes of intestinal absorption of xenobiotics. These are active transport, passive diffusions, pinocytosis, filtration through "pores," and lymphatic absorption. The passive diffusion is major process for transport of foreign chemicals across the intestine. Though the lymphatic absorption of drugs is not of any major therapeutic significance, the uptake of toxic chemicals such as 3-MC, benzpyrene, and DDT through lymphatics may enhance their toxicity, since they are distributed to other organ systems in the body without being metabolized by liver. A number of factors such as diet, motility of intestine, interference with gastrointestinal flora, changes in the rate of gastric emptying, age of the animal, and dissolution rate of xenobiotic can alter the rate of absorption of chemicals. Liver is the major site of metabolism of xenobiotics, but the contribution of intestinal metabolism of xenobiotic can influence the overall bioavailability of chemicals. The xenobiotic metabolizing enzymes located in endoplasmic reticulum of intestine possess biochemical characteristics similar to that of liver. In general, the rate of metabolism of xenobiotics by intestinal microsomal preparation is lower than that observed with similar hepatic microsomal preparations. The in vitro intestinal metabolism of xenobiotics is affected by several factors including age, sex, diurnal variations, species, and nutritional status of the animal. The intestinal xenobiotic metabolizing enzymes are stimulated by the pretreatment of animals with foreign chemicals, but this depends on the route of administration of chemicals, drug substrate and the animal species used. Rabbit intestinal drug metabolizing enzymes seem to be resistant to induction by foreign chemicals.
Topics: Animals; Animals, Newborn; Biological Availability; Biological Transport, Active; Circadian Rhythm; Diffusion; Enzyme Induction; Feeding Behavior; Inactivation, Metabolic; Intestinal Absorption; Intestinal Mucosa; Liver; Microsomes; Pharmaceutical Preparations
PubMed: 540626
DOI: 10.1289/ehp.793361 -
Biochimica Et Biophysica Acta Feb 2013Although at low concentrations, arsenic commonly occurs naturally as a local geological constituent. Whereas both arsenate and arsenite are strongly toxic to life, a... (Review)
Review
Although at low concentrations, arsenic commonly occurs naturally as a local geological constituent. Whereas both arsenate and arsenite are strongly toxic to life, a number of prokaryotes use these compounds as electron acceptors or donors, respectively, for bioenergetic purposes via respiratory arsenate reductase, arsenite oxidase and alternative arsenite oxidase. The recent burst in discovered arsenite oxidizing and arsenate respiring microbes suggests the arsenic bioenergetic metabolisms to be anything but exotic. The first goal of the present review is to bring to light the widespread distribution and diversity of these metabolizing pathways. The second goal is to present an evolutionary analysis of these diverse energetic pathways. Taking into account not only the available data on the arsenic metabolizing enzymes and their phylogenetical relatives but also the palaeogeochemical records, we propose a crucial role of arsenite oxidation via arsenite oxidase in primordial life. This article is part of a Special Issue entitled: The evolutionary aspects of bioenergetic systems.
Topics: Alcaligenes faecalis; Arsenate Reductases; Arsenic; Energy Metabolism; Oxidation-Reduction; Oxidoreductases; Protein Conformation
PubMed: 22982475
DOI: 10.1016/j.bbabio.2012.08.007 -
Journal of Chronic Diseases 1983The kinetics of drugs are known to change in the elderly. The most unequivocal example is the decrease in renal drug clearance. Yet, few studies have been published on...
The kinetics of drugs are known to change in the elderly. The most unequivocal example is the decrease in renal drug clearance. Yet, few studies have been published on the renal clinically important impairment of drug metabolism occurs in the elderly, and the effect of age per se cannot easily be discerned because a number of other factors that affect drug metabolism change with age (dietary and smoking habits, disease, drug interactions, ect.). In each age group there is a marked interindividual variation in the metabolic clearance of drugs leading to pronounced differences in steady-state plasma concentrations at fixed dosage-schedules. For drugs with a narrow therapeutic range it is important to avoid standard doses in slow metabolizers. This phenotype is at risk to develop adverse drug reactions unless the dose is reduced. It may be particularly important to recognize the slow metabolizer phenotype among the elderly, who may have exaggerated drug response due to physiological and pharmacodynamic reasons.
Topics: Aged; Aging; Enzymes; Humans; Kidney; Kinetics; Metabolic Clearance Rate; Models, Genetic; Pharmaceutical Preparations; Phenotype
PubMed: 6848546
DOI: 10.1016/0021-9681(83)90040-1 -
Food Microbiology Apr 2012The microbial degradation of proteins, peptides and amino acids generates volatiles involved in the typical flavor of dry fermented sausage. The ability of three...
The microbial degradation of proteins, peptides and amino acids generates volatiles involved in the typical flavor of dry fermented sausage. The ability of three Lactobacillus sakei strains to form aroma compounds was investigated. Whole resting cells were fermented in phosphate buffer with equimolar amounts of substrates consisting of dipeptides, tetrapeptides and free amino acids, respectively. Dipeptides disappeared quickly from the solutions whereas tetrapeptides were only partially degraded. In both approaches the concentration of free amino acids increased in the reaction mixture but did not reach the equimolar amount of the initial substrates. When free amino acids were fed to the bacteria their levels decreased only slightly. Although peptides were more rapidly degraded and/or transported into the cells, free amino acids produced higher amounts of volatiles. It is suggested, that after transport into the cell peptides are only partially hydrolyzed to their amino acids, while the rest is metabolized via alternative metabolic pathways. The three L. sakei strains differed to some extend in their ability to metabolize the substrates to volatile compounds. In a few cases this was due to the position of the amino acids within the peptides. Compared to other starter cultures used for the production of dry fermented sausages, the metabolic impact of the L. sakei strains on the formation of volatiles was very low.
Topics: Amino Acids; Animals; Cattle; Dipeptides; Fermentation; Lactobacillus; Meat Products; Oligopeptides
PubMed: 22202875
DOI: 10.1016/j.fm.2011.07.007 -
Annual Review of Pharmacology and... 1984The pharmacokinetics of PCBs are complicated by numerous factors, not the least of which is the existence of up to 209 different chlorinated biphenyls. Whereas all PCB... (Review)
Review
The pharmacokinetics of PCBs are complicated by numerous factors, not the least of which is the existence of up to 209 different chlorinated biphenyls. Whereas all PCB congeners are highly lipophilic and most are readily absorbed and rapidly distributed to all tissues, PCBs are cleared from tissues at very different rates, and the same congeners may be cleared at different rates by different species. With the exception of special situations in which PCBs may be passively eliminated in lipid sinks, e.g. milk or eggs, clearance is minimal prior to metabolism to more polar compounds. Rates of PBC metabolism vary greatly with species and with the degree and positions of chlorination. Mammals metabolize these compounds most rapidly, but even among mammalian species rates of metabolism vary greatly. In all species studied, the more readily metabolized chlorinated biphenyls have adjacent unsubstituted carbon atoms in the 3-4 positions. Congeners that do not have adjacent unsubstituted carbon atoms may be metabolized very slowly and are therefore cleared very slowly. These PCBs not readily cleared concentrate in adipose tissue. A physiologic pharmacokinetic model best illustrates how the concentrations of PCBs in all tissues approach equilibrium with the blood and with one another. Thus, the model illustrates how a depot of PCBs in any tissue, e.g. adipose tissue, will result in exposure of all tissues in proportion to the respective tissue/blood ratios and the body burden. The disposition of a number of PCBs in the rate has been accurately described by a physiologic model, and the model has been extrapolated to predict the disposition of these same PCBs in the mouse (58). Therefore, the physiologic pharmacokinetic model is believed to offer the best opportunity to extrapolate data obtained with laboratory animals to predict the disposition of PCBs in other species, including man. Most of the parameters of a model of PCB disposition in man are available or could be estimated. The major limitation to the construction of such a model is the absence of accurate estimates of metabolic clearance of individual PCBs by man. Accurate estimates of metabolic clearance depend on development of suitable in vitro methods to accurately predict clearance in vivo.
Topics: Animals; Biotransformation; Eggs; Feces; Humans; Kinetics; Milk; Models, Biological; Polychlorinated Biphenyls; Species Specificity; Tissue Distribution
PubMed: 6428301
DOI: 10.1146/annurev.pa.24.040184.000505 -
Drug Metabolism and Disposition: the... Jun 2019Cytochrome P450 family 2 subfamily C member 19 (CYP2C19), in liver, plays important roles in terms of drug metabolism. It is known that CYP2C19 poor metabolizers (PMs)...
Cytochrome P450 family 2 subfamily C member 19 (CYP2C19), in liver, plays important roles in terms of drug metabolism. It is known that CYP2C19 poor metabolizers (PMs) lack CYP2C19 metabolic capacity. Thus, unexpected drug-induced liver injury or decrease of drug efficacy would be caused in CYP2C19 substrate-treated CYP2C19 PMs. However, it is difficult to evaluate the safety and effectiveness of drugs and candidate compounds for CYP2C19 PMs because there is currently no model for this phenotype. Here, using human induced pluripotent stem cells (human iPS cells) and our highly efficient genome-editing and hepatocyte differentiation technologies, we generated CYP2C19-knockout human iPS cell-derived hepatocyte-like cells (CYP2C19-KO HLCs) as a novel CYP2C19 PM model for drug development and research. The gene expression levels of hepatocyte markers were similar between wild-type iPS cell-derived hepatocyte-like cells (WT HLCs) and CYP2C19-KO HLCs, suggesting that CYP2C19 deficiency did not affect the hepatic differentiation potency. We also examined CYP2C19 metabolic activity by measuring -mephenytoin metabolites using ultra-performance liquid chromatography-tandem mass spectrometry. The CYP2C19 metabolic activity was almost eliminated by CYP2C19 knockout. Additionally, we evaluated whether clopidogrel (CYP2C19 substrate)-induced liver toxicity could be predicted using our model. Unexpectedly, there was no significant difference in cell viability between clopidogrel-treated WT HLCs and CYP2C19-KO HLCs. However, the cell viability in clopidogrel- and ketoconazole (CYP3A4 inhibitor)-treated CYP2C19-KO HLCs was significantly enhanced as compared with that in clopidogrel- and DMSO-treated CYP2C19-KO HLCs. This result suggests that CYP2C19-KO HLCs can predict clopidogrel-induced liver toxicity. We succeeded in generating CYP2C19 PM model cells using human iPS cells and genome-editing technologies for pharmaceutical research. SIGNIFICANCE STATEMENT: Although unexpected drug-induced liver injury or decrease of drug efficacy would be caused in CYP2C19 substrate-treated CYP2C19 poor metabolizers, it is difficult to evaluate the safety and effectiveness of drugs and candidate compounds for CYP2C19 poor metabolizers because there is currently no model for this phenotype. Using human iPS cells and our highly efficient genome editing and hepatocyte differentiation technologies, we generated CYP2C19-knockout human iPS cell-derived hepatocyte-like cells as a novel CYP2C19 poor metabolizer model for drug development and research.
Topics: Cell Differentiation; Cell Line; Cell Survival; Chemical and Drug Induced Liver Injury; Clopidogrel; Cytochrome P-450 CYP2C19; Hepatocytes; Humans; Induced Pluripotent Stem Cells; Ketoconazole; Liver; Metabolic Clearance Rate
PubMed: 30962288
DOI: 10.1124/dmd.119.086322 -
Nutrients Nov 2021Diabetes remains one of the leading causes of deaths and co-morbidities in the world, with tremendous human, social and economic costs. Therefore, despite therapeutics... (Review)
Review
Diabetes remains one of the leading causes of deaths and co-morbidities in the world, with tremendous human, social and economic costs. Therefore, despite therapeutics and technological advancements, improved strategies to tackle diabetes management are still needed. One of the suggested strategies is the consumption of (poly)phenols. Positive outcomes of dietary (poly)phenols have been pointed out towards different features in diabetes. This is the case of ellagitannins, which are present in numerous foodstuffs such as pomegranate, berries, and nuts. Ellagitannins have been reported to have a multitude of effects on metabolic diseases. However, these compounds have high molecular weight and do not reach circulation at effective concentrations, being metabolized in smaller compounds. After being metabolized into ellagic acid in the small intestine, the colonic microbiota hydrolyzes and metabolizes ellagic acid into dibenzopyran-6-one derivatives, known as urolithins. These low molecular weight compounds reach circulation in considerable concentrations ranging until micromolar levels, capable of reaching target tissues. Different urolithins are formed throughout the metabolization process, but urolithin A, isourolithin A, and urolithin B, and their phase-II metabolites are the most frequent ones. In recent years, urolithins have been the focus of attention in regard to their effects on a multiplicity of chronic diseases, including cancer and diabetes. In this review, we will discuss the latest advances about the protective effects of urolithins on diabetes.
Topics: Biological Availability; Coumarins; Diabetes Mellitus; Fruit; Humans; Hydrolyzable Tannins; Nuts; Pomegranate; Protective Agents
PubMed: 34959837
DOI: 10.3390/nu13124285 -
Microbiology (Reading, England) Aug 1994The metabolic routes of substrate catabolism by intact cells of H. pylori have been investigated by 13C NMR. Real time analyses of metabolic transformations under... (Comparative Study)
Comparative Study
The metabolic routes of substrate catabolism by intact cells of H. pylori have been investigated by 13C NMR. Real time analyses of metabolic transformations under anaerobic conditions have been obtained with dense cell suspensions incubated with 13C-labelled pyruvate and glucose. In addition, time point studies have been carried out with cells incubated under aerobic conditions. Anaerobically, pyruvate was rapidly metabolized to lactate, ethanol and acetate. In addition, alanine was produced in significant quantities by cells provided with a nitrogen source and the metabolic incorporation of nitrogen from urea was demonstrated. Under aerobic conditions acetate was the major oxidation product from pyruvate; no evidence was obtained for tricarboxylic acid cycle activity. Glucose was metabolized more slowly than pyruvate. Anaerobically, two major products were observed and identified as sorbitol and gluconate by gas chromatography/mass spectrometry. Evidence was obtained for the oxidation of glucose to acetate under aerobic conditions. The fate of the 13C label with glucose substrates labelled in different positions showed that this oxidation takes place via the Entner-Doudoroff pathway.
Topics: Aerobiosis; Anaerobiosis; Energy Metabolism; Glucose; Glycolysis; Helicobacter pylori; Magnetic Resonance Spectroscopy; Oxidation-Reduction; Pyruvates; Pyruvic Acid
PubMed: 7921258
DOI: 10.1099/13500872-140-8-2085 -
Toxicology and Applied Pharmacology Sep 2005The cytochrome P450 enzymes are highly expressed in the liver and are involved in the metabolism of xenobiotics. Because of the initiatives associated with the Human... (Review)
Review
The cytochrome P450 enzymes are highly expressed in the liver and are involved in the metabolism of xenobiotics. Because of the initiatives associated with the Human Genome Project, a great progress has recently been seen in the identification and characterization of novel extrahepatic P450s, including CYP2S1, CYP2R1, CYP2U1 and CYP2W1. Like the hepatic enzymes, these P450s may play a role in the tissue-specific metabolism of foreign compounds, but they may also have important endogenous functions. CYP2S1 has been shown to metabolize all-trans retinoic acid and CYP2R1 is a major vitamin D 25-hydroxylase. Regarding their metabolism of xenobiotics, much remains to be established, but CYP2S1 metabolizes naphthalene and it is likely that these P450s are responsible for metabolic activation of several different kinds of xenobiotic chemicals and contribute to extrahepatic toxicity and carcinogenesis.
Topics: Animals; Biotransformation; Cytochrome P-450 Enzyme System; Humans; Liver; Xenobiotics
PubMed: 15987645
DOI: 10.1016/j.taap.2004.12.022