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The Journal of Steroid Biochemistry and... May 2015CYP11A1 hydroxylates vitamin D3 producing 20S-hydroxyvitamin D3 [20(OH)D3] and 20S,23-dihydroxyvitamin D3 [20,23(OH)2D3] as the major and most characterized metabolites....
CYP11A1 hydroxylates vitamin D3 producing 20S-hydroxyvitamin D3 [20(OH)D3] and 20S,23-dihydroxyvitamin D3 [20,23(OH)2D3] as the major and most characterized metabolites. Both display immuno-regulatory and anti-cancer properties while being non-calcemic. A previous study indicated 20(OH)D3 can be metabolized by rat CYP24A1 to products including 20S,24-dihydroxyvitamin D3 [20,24(OH)2D3] and 20S,25-dihydroxyvitamin D3, with both producing greater inhibition of melanoma colony formation than 20(OH)D3. The aim of this study was to characterize the ability of rat and human CYP24A1 to metabolize 20(OH)D3 and 20,23(OH)2D3. Both isoforms metabolized 20(OH)D3 to the same dihydroxyvitamin D species with no secondary metabolites being observed. Hydroxylation at C24 produced both enantiomers of 20,24(OH)2D3. For rat CYP24A1 the preferred initial site of hydroxylation was at C24 whereas the human enzyme preferred C25. 20,23(OH)2D3 was initially metabolized to 20S,23,24-trihydroxyvitamin D3 and 20S,23,25-trihydroxyvitamin D3 by rat and human CYP24A1 as determined by NMR, with both isoforms showing a preference for initial hydroxylation at C25. CYP24A1 was able to further oxidize these metabolites in a series of reactions which included the cleavage of C23-C24 bond, as indicated by high resolution mass spectrometry of the products, analogous to the catabolism of 1,25(OH)2D3 via the C24-oxidation pathway. Similar catalytic efficiencies were observed for the metabolism of 20(OH)D3 and 20,23(OH)2D3 by human CYP24A1 and were lower than for the metabolism of 1,25(OH)2D3. We conclude that rat and human CYP24A1 metabolizes 20(OH)D3 producing only dihydroxyvitamin D3 species as products which retain biological activity, whereas 20,23(OH)2D3 undergoes multiple oxidations which include cleavage of the side chain.
Topics: Animals; Calcifediol; Dihydroxycholecalciferols; Humans; Hydroxylation; Oxidation-Reduction; Rats; Vitamin D; Vitamin D3 24-Hydroxylase
PubMed: 25727742
DOI: 10.1016/j.jsbmb.2015.02.010 -
Chemico-biological Interactions Apr 2009Drug metabolism can be a key determinant of drug toxicity. A nontoxic parent drug may be biotransformed by drug metabolizing enzymes to toxic metabolites (metabolic...
Drug metabolism can be a key determinant of drug toxicity. A nontoxic parent drug may be biotransformed by drug metabolizing enzymes to toxic metabolites (metabolic activation). Conversely, a toxic drug may be biotransformed to nontoxic metabolites (detoxification). The approaches to evaluate metabolism-based drug toxicity include the identification of toxic metabolites and the evaluation of toxicity in metabolically competent and metabolically compromised systems. A clear understanding of the role of drug metabolism in toxicity can aid the identification of risk factors that may potentiate drug toxicity, and may provide key information for the development of safe drugs.
Topics: Animals; Biotransformation; Drug Design; Drug Evaluation, Preclinical; Humans; Species Specificity; Toxicity Tests
PubMed: 19070611
DOI: 10.1016/j.cbi.2008.11.013 -
Frontiers in Immunology 2024Excess dietary fructose consumption has been long proposed as a culprit for the world-wide increase of incidence in metabolic disorders and cancer within the past... (Review)
Review
Excess dietary fructose consumption has been long proposed as a culprit for the world-wide increase of incidence in metabolic disorders and cancer within the past decades. Understanding that cancer cells can gradually accumulate metabolic mutations in the tumor microenvironment, where glucose is often depleted, this raises the possibility that fructose can be utilized by cancer cells as an alternative source of carbon. Indeed, recent research has increasingly identified various mechanisms that show how cancer cells can metabolize fructose to support their proliferating and migrating needs. In light of this growing interest, this review will summarize the recent advances in understanding how fructose can metabolically reprogram different types of cancer cells, as well as how these metabolic adaptations can positively support cancer cells development and malignancy.
Topics: Humans; Fructose; Neoplasms; Tumor Microenvironment; Animals; Cellular Reprogramming; Energy Metabolism; Metabolic Reprogramming
PubMed: 38711514
DOI: 10.3389/fimmu.2024.1375461 -
Environmental Health Perspectives Apr 1984The lung metabolizes a wide variety of xenobiotics and, in the process, forms products that may be more or less toxic than the parent compound. The consequence of... (Review)
Review
The lung metabolizes a wide variety of xenobiotics and, in the process, forms products that may be more or less toxic than the parent compound. The consequence of metabolism, activation or detoxication, is a function of the nature of the substrate and of the characteristics and concentrations of the enzymes involved. As a result, the biotransformation of xenobiotics can lead to their excretion or to the formation of reactive products that produce deleterious effects by binding covalently to tissue macromolecules. Among the enzymes that metabolize xenobiotics, those associated with the cytochrome P-450-dependent monooxygenase system are probably the most important. The route by which a given substrate is metabolized in a tissue or cell is, to a great extent, determined by the types and concentrations of cytochrome P-450 isozymes present. We are just beginning to understand the distribution of these enzymes in lung and to appreciate the species and cellular differences that exist.
Topics: Animals; Biotransformation; Cytochrome P-450 Enzyme System; Humans; Inactivation, Metabolic; Isoenzymes; Lung; Mixed Function Oxygenases; Oxygenases; Pharmaceutical Preparations; Polycyclic Compounds; Substrate Specificity
PubMed: 6376107
DOI: 10.1289/ehp.8455359 -
Nature Apr 1994The decomposition of organic compounds by bacteria has been studied for almost a century, during which time selective enrichment culture has generated microorganisms...
The decomposition of organic compounds by bacteria has been studied for almost a century, during which time selective enrichment culture has generated microorganisms capable of metabolizing thousands of organic compounds. But attempts to obtain pure cultures of bacteria that can metabolize highly halogenated compounds, a large and important class of pollutants, have been largely unsuccessful. Polyhalogenated compounds are most frequently metabolized by anaerobic bacteria as a result of reductive dehalogenation reactions, the products of which are typically substrates for bacterial oxygenases. Complete metabolism of polyhalogenated compounds therefore necessitates the sequential use of anaerobic and aerobic bacteria. Here we combine seven genes encoding two multi-component oxygenases in a single strain of Pseudomonas which as a result metabolizes polyhalogenated compounds by means of sequential reductive and oxidative reactions to yield non-toxic products. Cytochrome P450cam monooxygenase reduces polyhalogenated compounds, which are bound at the camphor-binding site, under subatmospheric oxygen tensions. We find that these reduction products are oxidizable substrates for toluene dioxygenase. Perhalogenated chlorofluorocarbons also act as substrates for the genetically engineered strain.
Topics: Camphor 5-Monooxygenase; Cytochrome P-450 Enzyme System; Ethane; Genetic Engineering; Hydrocarbons, Chlorinated; Hydrocarbons, Halogenated; Mixed Function Oxygenases; Oxidation-Reduction; Oxygenases; Plasmids; Pseudomonas putida; Trichloroethylene
PubMed: 8145847
DOI: 10.1038/368627a0 -
Carbohydrate Polymers Jan 2023Hyaluronan is being investigated extensively as a biocompatible and biodegradable material for use in biomedical applications. While the derivatization of hyaluronan...
Hyaluronan is being investigated extensively as a biocompatible and biodegradable material for use in biomedical applications. While the derivatization of hyaluronan broadens its potential therapeutic use, the pharmacokinetics and metabolization of the derivatives must be thoroughly investigated. The fate of intraperitoneally-applied native and lauroyl-modified hyaluronan films with varying degrees of substitution was investigated in-vivo employing an exclusive stable isotope-labelling approach and LC-MS analysis. The materials were gradually degraded in peritoneal fluid, lymphatically absorbed, preferentially metabolized in the liver and eliminated without any observable accumulation in the body. Hyaluronan acylation prolongs its presence in the peritoneal cavity depending on the degree of substitution. The safety of acylated hyaluronan derivatives was confirmed via a metabolic study that revealed its degradation into non-toxic metabolites, i.e. native hyaluronan and free fatty acid. Stable isotope-labelling with LC-MS tracking comprises a high-quality procedure for the investigation of the metabolism and biodegradability of hyaluronan-based medical products in-vivo.
Topics: Hyaluronic Acid; Acylation; Chromatography, Liquid; Fatty Acids, Nonesterified; Isotopes
PubMed: 36876812
DOI: 10.1016/j.carbpol.2022.120201 -
Pharmaceutical Research Aug 1995A detailed investigation of the metabolic routes and rates of Dyn A1-13 in human blood and plasma was performed.
PURPOSE
A detailed investigation of the metabolic routes and rates of Dyn A1-13 in human blood and plasma was performed.
METHODS
Human plasma was incubated at 37 degrees C with dynorphin A 1-13 (Dyn A1-13, 15-20 microM). The generated dynorphin fragments were separated by a new ion-pair chromatographic method and identified by matrix assisted laser desorption mass spectroscopy. The kinetic behavior of parent compound and metabolites was evaluated in the absence and presence of enzyme inhibitors.
RESULTS
The major plasma metabolites of Dyn A1-13 were Dyn A1-12, A2-12, A4-12 and A4-8. Further metabolites were Dyn A2-13, A3-13, A3-12, A5-12, A6-12, A7-12, A1-10, A2-10, A2-8 and A3-8. At 37 degrees C, Dyn A1-13 had a half-life of less than one minute in plasma and blood. Plasma half-lives of major metabolites ranged between 0.5 and 4 min. Inter- and intra-individual differences in healthy volunteers were 30% (c.v.). Dyn A1-13 is mainly metabolized by carboxypeptidases to Dyn A1-12 (80%) and by aminopeptidases to Dyn A2-13 (15%). Dyn A1-12 and Dyn A2-13 are predominantly converted into Dyn A2-12 (67% of Dyn A1-13). Subsequent metabolic steps yield Dyn A3-12 (16%), Dyn A4-12 (37%) and Dyn A4-8 (33%). Aminopeptidases generate Dyn A2-12, A3-12, A4-12, A5-12. ACE metabolizes Dyn A1-12 (19%), A2-12 (33%), A3-12 (34%) and A4-12 (46%). Bestatin-sensitive endopeptidases (possibly endopeptidase 24.11) metabolize 30% of Dyn A2-12. Dyn A4-8 is formed via Dyn A4-12 (23% of Dyn A4-12) and Dyn A2-10 (37% of Dyn A2-10).
CONCLUSIONS
The combination of enzyme inhibition experiments and noncompartmental kinetic analysis proved to be a powerful tool for the detailed evaluation of the metabolic fate of Dyn A1-13 in human blood and plasma.
Topics: Adult; Analgesics, Opioid; Biotransformation; Chromatography, High Pressure Liquid; Dynorphins; Enzyme Inhibitors; Half-Life; Humans; In Vitro Techniques; Male; Mass Spectrometry; Molecular Weight; Peptide Fragments
PubMed: 7494829
DOI: 10.1023/a:1016211910107 -
Xenobiotica; the Fate of Foreign... Apr 19921. The metabolism of albendazole (ABZ), albendazole sulphoxide (ABZSO) and albendazole sulphone (ABZSO2) by ruminal, abomasal and ileal fluids of sheep and cattle was... (Comparative Study)
Comparative Study
1. The metabolism of albendazole (ABZ), albendazole sulphoxide (ABZSO) and albendazole sulphone (ABZSO2) by ruminal, abomasal and ileal fluids of sheep and cattle was investigated under anaerobic conditions in vitro. 2. None of the compounds was metabolically changed by incubation with abomasal fluids of sheep and cattle. 3. ABZ and ABZSO were extensively metabolized by sheep and cattle ruminal and ileal fluids. ABZSO2 was unaffected by incubation with these gastrointestinal fluids. 4. The rate of ABZ oxidation into ABZSO was greater for cattle ruminal and ileal fluids than for sheep fluids. 5. ABZSO was reduced back to ABZ by ruminal and ileal fluids of both species. This reducing activity was significantly higher for both ruminal and ileal fluids of sheep compared with those of cattle.
Topics: Abomasum; Albendazole; Animals; Anthelmintics; Body Fluids; Cattle; Inactivation, Metabolic; Intestinal Mucosa; Oxidation-Reduction; Rumen; Sheep; Stomach, Ruminant
PubMed: 1523862
DOI: 10.3109/00498259209046653 -
Pharmacology & Therapeutics 1993Polymorphisms have been detected in a variety of xenobiotic-metabolizing enzymes at both the phenotypic and genotypic level. In the case of four enzymes, the cytochrome... (Review)
Review
Polymorphisms have been detected in a variety of xenobiotic-metabolizing enzymes at both the phenotypic and genotypic level. In the case of four enzymes, the cytochrome P450 CYP2D6, glutathione S-transferase mu, N-acetyltransferase 2 and serum cholinesterase, the majority of mutations which give rise to a defective phenotype have now been identified. Another group of enzymes show definite polymorphism at the phenotypic level but the exact genetic mechanisms responsible are not yet clear. These enzymes include the cytochromes P450 CYP1A1, CYP1A2 and a CYP2C form which metabolizes mephenytoin, a flavin-linked monooxygenase (fish-odour syndrome), paraoxonase, UDP-glucuronosyltransferase (Gilbert's syndrome) and thiopurine S-methyltransferase. In the case of a further group of enzymes, there is some evidence for polymorphism at either the phenotypic or genotypic level but this has not been unambiguously demonstrated. Examples of this class include the cytochrome P450 enzymes CYP2A6, CYP2E1, CYP2C9 and CYP3A4, xanthine oxidase, an S-oxidase which metabolizes carbocysteine, epoxide hydrolase, two forms of sulphotransferase and several methyltransferases. The nature of all these polymorphisms and possible polymorphisms is discussed in detail, with particular reference to the effects of this variation on drug metabolism and susceptibility to chemically-induced diseases.
Topics: Animals; Humans; Metabolism; Polymorphism, Genetic
PubMed: 8361990
DOI: 10.1016/0163-7258(93)90053-g -
Applied and Environmental Microbiology Nov 1994The recombinant bacterium Pseudomonas putida G786(pHG-2) metabolizes pentachloroethane to glyoxylate and carbon dioxide, using cytochrome P-450CAM and toluene...
The recombinant bacterium Pseudomonas putida G786(pHG-2) metabolizes pentachloroethane to glyoxylate and carbon dioxide, using cytochrome P-450CAM and toluene dioxygenase to catalyze consecutive reductive and oxidative dehalogenation reactions (L.P. Wackett, M.J. Sadowsky, L.N. Newman, H.-G. Hur, and S. Li, Nature [London] 368:627-629, 1994). The present study investigated metabolism of brominated and chlorofluorocarbon compounds by the recombinant strain. Under anaerobic conditions, P. putida G786(pHG-2) reduced 1,1,2,2-tetrabromoethane, 1,2-dibromo-1,2-dichloroethane, and 1,1,1,2-tetrachloro-2,2-difluoroethane to products bearing fewer halogen substituents. Under aerobic conditions, P. putida G786(pHG-2) oxidized cis- and trans-1,2-dibromoethenes, 1,1-dichloro-2,2-difluoroethene, and 1,2-dichloro-1-fluoroethene. Several compounds were metabolized by sequential reductive and oxidative reactions via the constructed metabolic pathway. For example, 1,1,2,2-tetrabromoethane was reduced by cytochrome P-450CAM to 1,2-dibromoethenes, which were subsequently oxidized by toluene dioxygenase. The same pathway metabolized 1,1,1,2-tetrachloro-2,2-difluoroethane to oxalic acid as one of the final products. The results obtained in this study indicate that P. putida G786(pHG-2) metabolizes polyfluorinated, chlorinated, and brominated compounds and further demonstrates the value of using a knowledge of catabolic enzymes and recombinant DNA technology to construct useful metabolic pathways.
Topics: Aerobiosis; Anaerobiosis; Chlorofluorocarbons; Cytochrome P-450 Enzyme System; Hydrocarbons, Brominated; Oxygenases; Pseudomonas putida; Recombination, Genetic; Species Specificity
PubMed: 7993096
DOI: 10.1128/aem.60.11.4148-4154.1994