Studies on the metabolism of iron-containing proteins with radioactive carbon and iron.
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Carbon↗
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Results for “CARBON AND COMPOUNDS, RADIOACTIVE”
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Biotransformation of norgestimate in women.
The metabolism of norgestimate (ORF-10131; 14C-d-13-ethyl-17-acetoxy-18,19-dinor-17 alpha-pregn-4-en-20- yn -3-oxime) was studied in humans. Compound labeled with carbon-14 in the 17 alpha-ethynyl group was administered to four female subjects. An average of 46.8 percent of the administered radioactivity was excreted in the urine and 36.8 percent in the feces over a two-week collection period. About 12 percent of the urinary radioactivity represented freely extractable metabolites and another 57 percent consisted of extractable material released by enzyme hydrolysis. The ethynylated metabolites of norgestimate were separated from endogenous compounds and non- ethynylated metabolites by silver- sulfoethyl cellulose column chromatography. Metabolites were subsequently isolated by high performance liquid chromatography and thin layer chromatography. The identification of five urinary metabolites was accomplished by combined gas-liquid chromatography/mass spectrometry. These metabolites include norgestrel, 16 beta- hydroxynorgestrel , 2 alpha- hydroxynorgestrel , 3 alpha, 5 beta- tetrahydronorgestrel , and a fifth trihydroxylated metabolite of undetermined stereochemical configuration; 3,16-dihydroxy-5- tetrahydronorgestrel .
Biotransformation↗
Heterocyclic bis-cations as starting hits for design of inhibitors of the bifunctional enzyme histidine-containing protein kinase/phosphatase from Bacillus subtilis.
The main mechanism of carbon catabolite repression/activation in low-guanine and low-cytosine Gram-positive bacteria seems to involve phosphorylation of HPr (histidine-containing protein) at Ser-46 by the ATP-dependent HPr kinase, which in Bacillus subtilis, Lactobacillus casei, and Staphylococcus xylosus also exhibits phosphatase activity and is thus a bifunctional enzyme (HPrK/P). Since deficiency of HPrK/P in S. xylosus, L. casei, and B. subtilis mutants leads to severe growth defects, inhibitors of the enzyme could form a new family of antibiotic drugs. The aim of the study was to screen an in-house chemical library for identification of hits as inhibitors of HPrK/P in B. subtilis and to further extract additional information of structural features from hit optimization using a radioactive in vitro assay. A symmetrical bis-cationic compound LPS 02-10-L-D09 (2a) with a 12-carbon alkyl linker bridging the two 2-aminobenzimidazole moieties was identified as a non-ATP mimetic compound exhibiting an EC(50) value of 10 microM in a kinase assay with HPr as substrate. The substance also inhibited the phosphatase activity of HPrK/P triggered by the addition of inorganic phosphate. Similar results were obtained with 2a and catabolite repression HPr, which, like HPr, can be phosphorylated at Ser-46 by HPrK/P and is involved in catabolite repression. Structure-activity relationship analysis indicated the importance in its structure of a substituted 2-aminobenzimidazole. This typical heterocycle is linked through a C12 alkyl chain to a second scaffold that can bear a cationic or a noncationic moiety but in all cases should present an aromatic ring in its vicinity.
Adenosine Triphosphate↗
Biosynthesis of streptothricin antibiotics. I. Incorporation of 14C-labeled compound into racemomycin-A and distribution of radioactivity.
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Anti-Bacterial Agents↗
Thymidine incorporation into Rhizobium meliloti.
Thymidine is rapidly catabolized to thymine, beta-aminoisobutyric acid, and carbon dioxide by Rhizobium meliloti cells. The incorporation of labelled thymidine into the DNA of R. meliloti cells can be enhanced by the addition of low concentrations (10-20 micrograms/mL) of deoxyadenosine or other nucleosides (adenosine, uridine, guanosine). However, at high concentrations ( greater than 50 micrograms/mL) these compounds inhibit thymidine incorporation. Conditions to obtain highly radioactive DNA of Rhizobium are described.
Carbon Radioisotopes↗
Rates of mineralization of trace concentrations of aromatic compounds in lake water and sewage samples.
The rates of mineralization of phenol, benzoate, benzylamine, p-nitrophenol, and di(2-ethylhexyl) phthalate added to lake water at concentrations ranging from a few picograms to nanograms per milliliter were directly proportional to chemical concentration. The rates were still linear at levels of <1 pg of phenol or p-nitrophenol per ml, but it was less than the predicted value at 1.53 pg of 2,4-dichlorophenoxyacetate per ml. Mineralization of 2,4-dichlorophenoxyacetate was not detected in samples of lake water containing 200 ng of the chemical per ml. The slope of a plot of the rate of phenol mineralization in samples of three lakes as a function of its initial concentration was lower at levels of 1 to 100 mug/ml than at higher concentrations. In lake water and sewage supplemented with <60 ng of C-labeled benzoate or phenylacetate per ml, 95 to 99% of the radioactivity disappeared from solution, indicating that the microflora assimilated little or none of the carbon. The extent of mineralization of some compounds in samples of two lakes and sewage was least in the water with the lowest nutrient levels. No mineralization of 2,4-dichlorophenoxyacetate and the phthalate ester was observed in samples of an oligotrophic lake. These data suggest that mineralization of some chemicals at concentrations of <1 mug/ml is the result of activities of organisms different from those functioning at higher concentrations or of organisms that metabolize the chemicals at low concentrations but assimilate little or none of the substrate carbon.
Journal Article↗
THE INCORPORATION OF CARBON DIOXIDE INTO MILK CITRATE IN THE ISOLATED PERFUSED GOAT UDDER.
1. Isolated perfused goat udders supplied with glucose, acetate and amino acids were infused for several hours with NaH(14)CO(3). 2. Lactose, milk-fat fatty acids and glycerol had very little radioactivity. The specific radioactivity (counts./min./mg. of C) of milk citrate was 9-16% that of the carbon dioxide in the perfusion fluid and 19% that estimated for tissue carbon dioxide. The specific radioactivity of tissue citrate resembled that of milk citrate. 3. The radioactivity in citrate was predominantly in C-6, suggesting some carboxylation of alpha-oxoglutarate in addition to carboxylation of C(3) compounds. 4. [1-(14)C]Glutamate was infused in a similar experiment, and milk citrate radioactivity was predominantly in C-1+C-5. 5. The results are discussed in relation to the contribution of glucose and acetate carbon to citrate. The implications of the carboxylation of alpha-oxoglutarate are considered.
Acetates↗
The Biosynthesis of delta-Aminolevulinic Acid in Higher Plants: II. Formation of C-delta-Aminolevulinic Acid from Labeled Precursors in Greening Plant Tissues.
delta-Aminolevulinic acid was accumulated by greening cucumber (Cucumis sativus L. var. Alpha green) cotyledons, barley (Hordeum sativum var. Numar) leaves, and bean (Phaseolus vulgaris L. var. Red Kidney) leaves in the presence of various (14)C-labeled precursors and levulinic acid, a competitive inhibitor of delta-aminolevulinic acid dehydrase. The radioactivity in the accumulated delta-aminolevulinic acid was measured.The most effective labeled precursors were the 5 carbon dicarboxylic compounds glutamate, glutamine, and alpha-ketoglutarate. (14)C-Labeled glycine and succinate were relatively poor. The carboxyl and the methylene carbons of glycine were incorporated into delta-aminolevulinic acid to about equal extent. The carboxyl carbon of glutamate was incorporated almost as well as the internal carbons of the same compound. These results are inconsistent with the succinyl CoA-glycine succinyl transferase (delta-aminolevulinic acid synthetase) mode of delta-aminolevulinic acid production.When the same experiments were performed on turkey blood (which, as avian blood in general, possesses delta-aminolevulinic acid synthetase), delta-aminolevulinic acid was labeled most effectively from glycine-2-(14)C, moderately well from glycine-1-(14)C and glutamate-3,4-(14)C and not at all from glutamate-1-(14)C.It appears probable that greening higher plant tissues possess an alternate route to delta-aminolevulinic acid in which the carbon skeleton of glutamate (and alpha-ketoglutarate) is incorporated intact into the first committed metabolite of the chlorophyll pathway.
Journal Article↗
Pharmacokinetics of picumast after administration of 14C-picumast dihydrochloride in dogs, rats, rabbits and monkeys.
In dogs, rats, monkeys and rabbits, picumast (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarin ) is eliminated from the plasma by metabolic clearance. Its main metabolic pathway is oxidation of the 3-methyl group of the coumarin ring. After oral administration, the parent compound accounted for less than 15% of the concentration of radioactivity in the plasma. In rats the hydroxylation product M2 was the main metabolite in the plasma; in the other species it was the carbonic acid M1. The hydroxylation of picumast was highly saturable, whereas further oxidation was independent of the dose in dogs and only slightly dose-dependent in rats. Picumast, M1 and M2 are pharmacologically active and potentially toxic. The sum of all three was defined as active compounds. The renal clearance of the active compounds, particularly of picumast, was very low. The terminal half-lives of the active compounds varied between 11 h in rats and 26 h in monkeys. The low plasma concentrations of other metabolites are at least partly due to their renal clearance. In dogs the bioavailability of the parent compound was 14%, the absorption of radioactivity 68%. Of radioactivity injected intravenously 54.8% was recovered from the faeces, 21.8% from the urine. The minimum toxic plasma concentrations of the active compounds were calculated from the minimum toxic dose (MTD) found in chronic or reproduction toxicity studies and the ratio Cl/f of total body clearance/bioavailability determined in the present investigations. The results showed that the differences between the MTDs in dogs and rats and on administration in rats by gavage or in the diet are largely due to differences in total body clearance and bioavailability.
Absorption↗
Gastric acid secretion and the expiration of radioactive carbon dioxide of carboxyl- 14 C-labelled histidine-loaded rats.
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Acetazolamide↗
Closo-dodecaborate(2-) as a linker for iodination of macromolecules. Aspects on conjugation chemistry and biodistribution.
Boron-containing compounds like closo-dodecaborate(2-) are in theory suitable for radioactive labeling with halogens. The boron-halogen bond is stronger than carbon-halogen bond and is not likely to be recognized by deiodinating enzymes in vivo. Peptides and proteins may be conjugated with various closo-dodecaborate(2-)-containing ligands, and thereafter, the conjugate can be iodinated. Since closo-dodecaborate(2-) is more avidly iodinated than tyrosine in moderately acidic media, such conjugates may be directly labeled on the boron part with radioisotopes of iodine using the standard Chloramine-T procedure. Mercapto-undecahydro-closo-dodecaborate(2-) (BSH) was reacted with the double bond of allyldextran to form a boronated dextran compound of the molecular size of about 70 kDa. This compound, in the text denoted as Dx-BS, and cesium dodecahydro-closo-dodecaborate(2-) were labeled using iodine-125. The two compounds were administered to rats in order to study their in vivo stability. The results indicate that iodinated Dx-BS is stable for about 20 h in vivo. The degradation rate, as indicated by thyroid uptake, was found low. [125I]Iodo-closo-dodecaborate(2-), which is a possible degradation product of [125I]Dx-BS-I, was rapidly excreted in urine without significant accumulation in any organ.
Animals↗
Histamine H1 receptors in human brain visualized in vivo by [11C]doxepin and positron emission tomography.
Histamine H1 receptors in the living human brain were visualized by positron emission tomography (PET) using [N-11C-methyl]-(E)-doxepin ([11C]doxepin). The regional distribution of the carbon-11-labeled compound in the brain corresponded well with that of the histamine H1 receptors measured in vitro using [3H]pyrilamine. The radioactivity in the brain was significantly reduced by intravenous pretreatment with d-chlorpheniramine (5 mg), a histamine H1 antagonist. The regional distribution of [11C]doxepin in the brain 45-90 min after its injection was almost the same as that of [11C]pyrilamine in the brain. These results indicate that [11C]doxepin is useful for measuring histamine H1 receptors in human brain by PET.
Adult↗
[Autoradiographic determinations of carbon-14-labeled monomers and residual monomers in the tissues of Wistar rats after implantation of cold-polymerizing polymethyl methacrylate (bone cement) (author's transl)].
Self-setting acrylics, named bone cement, are taken for the reconstruction of bone defects, for the fixation of endothesis and fractures. A disadvantage of these rapid-cure acrylic compounds is the toxicity of its monomer. Infraredspectrographic measurements showed an absolute content of 12,3 per cent monomer in an acrylic-resin-compound-implant. In order to perseive the incorporation of the diffused monomer after implantation of bone cement in rats, the monomer were marked with 14C (radioactive carbon). The autoradiographic examination revealed the excretion of the marked monomer in the urine and an accumulation in kidney, liver and lungs. The results were demonstrated.
Acrylic Resins↗
A simplified technique for the liquid scintillation measurement of radioactivity on paper chromatograms containing toluene-insoluble C-14-and H-3-labeled compounds.
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Benzofurans↗
Biosynthesis of phytoquinones. Biosynthetic origins of the nuclei and satellite methyl groups of plastoquinone, tocopherols and tocopherolquinones in maize shoots, bean shoots and ivy leaves.
1. By using dl-[ring-(14)C]phenylalanine, dl-[beta-(14)C]phenylalanine, dl-[alpha-(14)C]-tyrosine and dl-[beta-(14)C]tyrosine it was shown that in maize shoots (Zea mays) the nucleus and one nuclear methyl group of each of the following compounds, plastoquinone, gamma-tocopherol (aromatic nucleus) and alpha-tocopherolquinone, are formed from the nuclear carbon atoms and beta-carbon atom respectively of either exogenous phenylalanine or exogenous tyrosine. With ubiquinone only the aromatic ring of the amino acid is used in the synthesis of the quinone nucleus. Chemical degradation of plastoquinone and gamma-tocopherol molecules labelled from l-[U-(14)C]tyrosine established that a C(6)-C(1) unit directly derived from the amino acid is involved in the synthesis of these compounds. Radioactivity from [beta-(14)C]cinnamic acid is not incorporated into plastoquinone, tocopherols or tocopherolquinones, demonstrating that the C(6)-C(1) unit is not formed from any of the C(6)-C(1) phenolic acids associated with the metabolism of this compound. 2. The incorporation of radioactivity from l-[U-(14)C]tyrosine, dl-[beta-(14)C]tyrosine and dl-[U-(14)C]phenylalanine into bean shoots (Phaseolus vulgaris) and dl-[beta-(14)C]tyrosine and l-[Me-(14)C]methionine into ivy leaves (Hedera helix) was also investigated. Similar results were obtained to those reported for maize, except that in beans phenylalanine is only used for ubiquinone biosynthesis. This is attributed to the absence of phenylalanine hydroxylase from these tissues. In ivy leaves it is found that the beta-carbon atom of tyrosine gives rise to the 8-methyl group of delta-tocopherol, and it is suggested that for all other compounds examined it will give rise to the nuclear methyl group meta to the polyprenyl unit. 3. Preliminary investigations with the alga Euglena gracilis showed that in this organism ring-opening of tyrosine occurs to such an extent that the incorporation data from radiochemical experiments are meaningless. 4. The above results, coupled with previous observations, are interpreted as showing that in higher plants the nucleus of ubiquinone can be formed from either phenylalanine or tyrosine by a pathway involving as intermediates p-coumaric acid and p-hydroxybenzoic acid. Plastoquinone, tocopherols and alpha-tocopherolquinone are formed from p-hydroxyphenylpyruvate by a pathway in which the aromatic ring and C-3 of the side chain give rise respectively to the nucleus and to one nuclear methyl group. 5. Dilution experiments provided evidence that in maize shoots p-hydroxyphenylpyruvic acid and homogentisic acid (produced from p-hydroxyphenylpyruvic acid) are involved in plastoquinone biosynthesis, and presumably the biosynthesis of related compounds: however, other possible intermediates in the conversion including toluquinol (the aglycone of the proposed key intermediate) showed no dilution effects. Further, radioactivity from [Me-(14)C]toluquinol is not incorporated into any of the compounds examined. 6. Dilution experiments with 3,4-dihydroxybenzaldehyde and radioactive-labelling experiments with 3,4-dihydroxy[U-(14)C]benzoic acid demonstrated that these compounds are not involved in the biosynthesis of either ubiquinone or phylloquinone in maize shoots. 7. Evidence is also presented to show that in maize shoots ring-opening of the aromatic amino acids takes place. The suggestion is offered that this may take place via homogentisic acid, as in animals and some micro-organisms.
Amino Acids↗
Feline attractant, cis,trans-nepetalactone: metabolism in the domestic cat.
cis,trans-Nepetalactone, the biologically active component of catnip, was force-fed to the domestic cat. When the (14)C-labeled compound was fed, 86 to 94 percent of the radioactivity was recovered in the urine, 1 to 2 percent was found in the feces, and 1 to 12 percent was collected as carbon dioxide. The major (50 to 75 percent) metabolite was alpha-nepetalinic acid, which was excreted in the urine together with small amounts of dihydronepetalactone, unchanged cis,-trans-nepetalactone, and several unidentified compounds. No marked physiological or histological eflects were observed when 20 to 80 milligrams of cis, trans-nepetalactone was administered orally. This is the first report on the metabolism of a mammalian attractant.
Animal Feed↗
Synthesis, metabolism, and disposition of the antiinflammatory 3-[2-(4-methylphenyl)-thioethyl]-sydnone-5-14C in the rat.
The synthesis, as well as the in vivo and in vitro disposition, of 3-[2-(4-methylphenyl)thioethyl]-sydnone-5-14C (5) in the rat is described. After intraperitoneal injection of a single dose of 5 in female Sprague-Dawley rats, the distribution and excretion of radioactive substances was monitored (24 h). Radioactivity in the blood declined in a biphasic manner with half-lives of 0.55 and 15.2 h for the alpha- and beta-phase, respectively. About 8% of the administered radioactivity was detected in feces and approximately 90% in urine (24 h). In 3.75 h, 50% of the radio-dose was excreted in the urine. Tissue distribution studies demonstrated a selective uptake of radioactivity only by the adrenal glands and the ovaries. The radioactivity in these organs reached a maximum approximately 1 h after dosing and then declined rapidly. None of the parent drug was excreted from such a single dose (i.p. injection) which indicated rapid in vivo metabolism. Nor could there be found any metabolites related to the whole structure, for example, the sulfoxide or aromatic hydroxy compounds. The sydnone 5, its sulfoxide and unconjugated metabolites were detected and quantitated by GC/MS methodology using unlabelled authentic samples. Radioactive carbon dioxide was not detected during the in vivo or in vitro experiments, nor was it released from alkaline urine samples upon acidification. Radiolabelled urinary metabolites were glycolic acid-1-14C 9 (34%), its glycine conjugate 10 (52%) and 3-vinylsydnone-5-14C 11 (4%).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Radioactive methionine: determination, and distribution of radioactivity in the sulfur, methyl and 4-carbon moieties.
A simple and inexpensive method is described for isolation and determination of [14C]methionine in the non-protein fraction of tissues extensively labeled with 14C. The effectiveness of the method was demonstrated by isolation of non-protein [14C]methionine (as the carboxymethylsulfonium salt) of proven radiopurity from the plant Lemna which had been grown for a number of generations on [U-14C]sucrose and contained a 2000-fold excess of 14C in undefined non-protein compounds. To our knowledge, this is the first reported assay for radioactive methionine under these demanding conditions. This method also offers an attractive alternative to the use of more expensive and sophisticated equipment for assay of radioactive methionine under less demanding conditions. An advantage is that the isolated methioninecarboxymethylsulfonium salt is readily degraded to permit separate determination of radioactivity in the 4-carbon, methyl and sulfur moieties of methionine. During this work, a facile labilization of 3H attached to the (carboxy)methylene carbon of methioninecarboxymethylsulfonium salt was observed. This labilization is ascribed to formation of a sulfur ylid.
Carbon↗