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The precursor of the thiazole moiety of thiamin in Candida utilis was identified. Radioactive C-2, 3, 4, 5 and 6 of glucose was incorporated into C-4', 4, 5, 5' and 5" of the thiazole. This experiment shows that the precursor of the five carbon unit of thiazole is a 5-carbon compound such as ribose or ribulose derived from glucose.
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25-Azido[25-(3)H]norcholesten-3beta-ol, a radioactive photosensitive analog of cholesterol, was synthesized as a probe to study lipid-protein interactions [Stoffel, W. & Klotzbücher, R. (1978) Hoppe-Seyler's Z. Physiol Chem. 359, 199-209]. Upon UV irradiation a reactive nitrene is generated which can insert into carbon-hydrogen bonds of proteins to form covalent linkages. The compound has properties similar to those of cholesterol. When administered intravenously to rats it was transported to the liver, and within 4 hr it was found in all of the subcellular fractions, accounting for 8% of the microsomal sterol content. Concomitantly, it altered the activities of two membrane-bound enzymes. 3-Hydroxy-3-methylglutaryl (HMG)-CoA (NADPH) reductase [mevalonate:NADP(+) oxidoreductase (CoA-acylating), EC 1.1.1.34] activity was reduced to 20% of control values, and acyl-CoA:cholesterol acyltransferase (ACAT; acyl-CoA:cholesterol O-acyltransferase, EC 2.3.1.26) was stimulated at least 2-fold. Esterified products of the analog were found in both blood and liver, and no evidence was obtained for production of any hydroxylated or polar derivatives. UV irradiation of microsomes increased the radioactivity bound to the protein fraction and decreased it in the total lipid extract; in parallel a sharp decline in ACAT activity but unaltered HMG-CoA reductase activity was observed. These results are interpreted as a possible consequence of crosslinking of the sterol to the enzyme proteins and discussed in view of the evidence that HMG-CoA reductase is an extrinsic and ACAT an intrinsic membrane protein.
Choline acetyltransferase (EC 2.3.1.6) was studied in human cerebrospinal fluid and blood. Sensitivity, precision and reproducibility of the radioactive assay were evaluated with a homogenate from pig brain and with partially purified enzymes from bovine brain and human placenta. Contrary to other reports, with the assay used in the present study, choline acetyltransferase activity was not detectable in the cerebrospinal fluid or blood of 50 patients with various neurological disorders. Only a very slight but significant non-enzymatic formation of a radioactive product by concentrated cerebrospinal fluid was observed. Nonenzymatic but enzyme-like formation of acetylcholine by thiol reagents and other compounds is discussed.
Carbon-11 labeled (-)-methamphetamine and (-)-3,4-methylenedioxy-N-methamphetamine were synthesized by methylation of the corresponding desmethyl precursors with [11C]H3I in 40-60% yield in a synthesis time of 30 min from EOB with a specific activity of 0.5-1.2 Ci/microM. PET studies in a Rhesus monkey revealed that the uptakes of both compounds in different brain regions were similar, and the retention of radioactivity in these brain regions remained constant throughout the study for the former while it was washed out slowly for the latter. The half-life of (-)-3,4-methylenedioxy-N-methamphetamine in monkey brain was approximately 70 min. Analyses of arterial plasma by HPLC revealed that 50% of radioactivity in the plasma remained as (-)-methamphetamine while only 3% remained as (-)-3,4-methylenedioxy-N-methamphetamine at 60 min post-injection. These results suggest that the uptakes of both compounds in monkey brain are probably not receptor mediated. Rather, blood flow, lipophilicity of the compounds or other transport mechanisms may play a role in their uptakes.
The formation of alanine, glutamate, and aspartate from muscle was studied in the isolated perfused hindquarter of rats fasted for 48 h. Tracer doses of (14C) compounds with high specific activity were tested as precursors for the amino acids. Total amounts and radioactivities of the tested amino acids were determined. Alanine was produced more efficiently than glutamate and aspartate even if no exogenous substrate was offered. (14C) Pyruvate was most efficient as precursor of labeled alanine. However, labeled leucine, propionic acid, valine and fumaric acid also produced labeled alanine efficiently. The efficiency as precursor for labeled alanine seemed to be related to the ability to label intermediates in the citric acid cycle in the perfused muscle. From the relation between the ability to label alanine in the perfusion medium and lactate and succinate in the muscle it is suggested that pyruvate may be produced intramitochondrially and is efficiently transaminated to alanine in this compartment.
Distribution and balance studies with carbon-14-labeled amphotericin B methyl ester (AME) were carried out in mice. The radioactive AME was administered by either the intraperitoneal (i.p.) or intravenous (i.v.) route. In the organ distribution study, the percent radioactivity accumulating in the lung of i.v. treated mice at 1 hour after administration was about 150 times greater than that observed when the intrapertinoneal route was used. No accumulation of radioactivity with time was detected in the kidneys of either the i.v. or i.p. treated mice. After 4 days, about 51% of the total radioactivity was excreted into the urine and feces of mice after i.v. administration, but only about 15% of the total radioactivity was excreted in the case of mice receiving radioactive AME by the i.p. route. In the identification of the substances excreted in the urine, thin-layer chromatography (TLC), radioactivity, and bioautographic evidence suggest that there was no detectable de-esterification of AME to the parent compound in mice treated either intraperitoneally or intravenously with AME.
Many substances which do not react with DNA directly are metabolized into important DNA-modifying intermediates. We have devised a method for trapping these intermediates with 14C-labeled nucleosides contained in a synthetic polynucleotide. The polynucleotide structure protects the labeled nucleoside from metabolism; thus, it is unaltered when the polymer is incubated with a drug-metabolizing system. However, when the polymer is incubated with this system and a compound which can be metabolized into a reactive species, these intermediates are trapped by the 14C-labeled nucleoside and subsequently are detected as new peaks of radioactivity in a digest of the labeled polynucleotide. This system has been used to detect reactive intermediates of cyclophosphamide generated by a liver homogenate.
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Several studies have demonstrated the potential of p-[(18)F]MPPF as a radiopharmaceutical to study the 5-HT(1A) receptor family in animals and humans. A structural modification leading to a higher radioactive signal at an equipotent dose would greatly enhance this potential. With this goal, the desmethylated 4-(2'-methoxyphenyl)-1-[2'-[N-(2''-pyridinyl)-p-fluorobenzamido]ethyl]-piperazine (p-MPPF), identified as p-DMPPF, was synthesized, labeled with fluorine-18 and evaluated through ex vivo tissue distribution in rats. The new compounds p-DMPPF, p-DMPPNO(2), MEM-p-MPPF and MEM-p-MPPNO(2) were isolated and fully identified ((1)H and (13)C NMR, LC-MS). The final compound, p-[(18)F]DMPPF, was obtained ready for injection, with an overall radiochemical yield of 10% (EOB corrected) within 90 min and a specific activity of 62 GBq/mumol. Tissue distributions showed that the carbon-fluorine bond was stable in vivo and that this compound could cross the blood-brain barrier. For kidney, lung, heart, spleen, bone, testicle, liver and muscle, the percentage of injected dose per gram of tissue obtained with p-[(18)F]DMPPF was of the same order of magnitude as that of p-[(18)F]MPPF. The amount of radioactivity reaching the brain was much higher (approximately fivefold at 60 min) for p-[(18)F]DMPPF compared with p-[(18)F]MPPF, which was taken as reference. The distribution and specificity were in total agreement with the known localization of 5-HT(1A) receptors in rats. The radioactivity increase was more important for specific tissues (hippocampus and frontal cortex) than for cerebellum or striatum, leading to better contrast (hippocampus/cerebellum=5.8 at 60 min). The levels of metabolites found in plasma showed that p-[(18)F]DMPPF appears to be less metabolized than p-[(18)F]MPPF. p-[(18)F]DMPPF deserves further evaluation as a radiopharmaceutical candidate.
In order to study the tumor specificity of synthetic nonmetabolizing amino acids, 10 different 14C labeled alicyclic amino acids (3a-3j) were synthesized in high yield and with high specific radioactivity. Carbon-14 labeled alicyclic hydantoins (2a-2j) were synthesized from a small amount of radioactive potassium [14C] cyanide and corresponding ketones (1a-1j). Th 14C hydantoins (2a-2j) thus obtained were hydrolyzed without isolation to give 14C labeled alicyclic amino acids (3a-3j). The overall radiochemical yields of the amino acids (3a-3j) from potassium [14C] cyanide were 55.6-93.2% with radiochemical purity more than 99%. Specific activities of these 14C labeled compounds (3a-3j) were 209- 250 MBq/mmol (5.66-6.75 mCi/mmol). When non-radioactive potassium cyanide was not added as a carrier, 1-aminocyclopentane[14C]-carboxylic acid (3b) and 1-aminocyclooctane[14C]carboxylic acid (3e) were synthesized in the yield of 64.9 and 19.0% respectively with the specific activity exceed more than 1.85 GBq/mmol (50mCi/mmol).
Some octopamine (OA) agonists were found to suppress the calling behaviour and pheromone biosynthesis in vitro of the Indian meal moth, Plodia interpunctella (Hübner), a stored-product pest. Compounds were screened using a calling behaviour bioassay of female P interpunctella. Three active derivatives, with activity at the nanomolar level, were identified. In order of decreasing pheromonostatic activity these were: 2-(2-ethyl-6-methylanilino)oxazolidine > 2-(2,6-diethylanilino)thiazolidine > 2-(2,6-diethylanilino)oxazolidine. These compounds showed also in vitro inhibitory activities in de novo pheromone biosynthesis. Three-dimensional pharmacophore hypotheses were built from a set of 19 compounds. Among the ten common-featured models generated by the program Catalyst/HipHop, a hypothesis including a ring aromatic group (RA), a positive ionizable group (PI) and two hydrophobic aliphatic (HpA1) features was considered to be essential for inhibitory activity in the calling behaviour and pheromone biosynthesis in vitro. Active compounds mapped well onto all the RA, PI and HpA1 features of the hypothesis. Less-active compounds were shown not to achieve the energetically favourable conformation which was found in the active molecules in order to fit the 3-D common-feature pharmacophore models. The present studies demonstrate that inhibition of calling behaviour and PBAN-stimulated incorporation of radioactivity is by OA-agonistic activity.
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Time-resolved laser-induced fluorescence spectroscopy (TRLFS) and imaging spectromicroscopy (TRLFISM) were used to examine the chemical speciation of uranyl in contaminated subsurface sediments from the U.S. Department of Energy (U.S. DOE) Hanford Site, Washington. Spectroscopic measurements for contaminant U(VI) were compared to those from a natural, uranyl-bearing calcite (NUC) that had been found via X-ray absorption spectroscopy (XAS) to include uranyl in the same coordination environment as calcium. Spectral deconvolution of TRLFS measurements on the NUC revealed the unexpected presence of two distinct chemical environments consistent with published spectra of U(VI)-substituted synthetic calcite and aragonite. Apparently, some U(VI) substitution sites in calcite distorted to exhibit a local, more energetically favorable aragonite structure. TRLFS measurements of the Hanford sediments NP4-1 and NP1-6 were similar to the NUC in terms of peak positions and intensity, despite a small CaCO3 content (1.0 to 3.2 mass %). Spectral deconvolution of the sediments revealed the presence of U(VI) in calcite and aragonite structural environments. A third, unidentified U(VI) species was also present in the NP1-6 sediment. TRLFISM measurements at multiple locations in the different sediments displayed only minor variation, indicating a uniform speciation pattern. Collectively, the measurements implied that waste U(VI), long-resident beneath the sampled disposal pond (32 y), had coprecipitated within carbonates. These findings have major implications for the solubility and fate of contaminant U(VI).
Aqueous U(VI) reduction by hydrogen sulfide was investigated by batch experiments and speciation modeling; product analysis by transmission electron microscopy (TEM) was also performed. The molar ratio of U(VI) reduced to sulfide consumed, and the TEM result suggested that the reaction stoichiometry could be best represented by UO2(2+) + HS- = UO2+ S* + H+. At pH 6.89 and total carbonate concentration ([CO32-]T) of 4.0 mM, the reaction took place according to the following kinetics: -d[U(VI)]/dt = 0.0103[U(VI)][S2-]T0.54 where [U(VI)] is the concentration of hexavalent uranium, and [S2-]T is the total concentration of sulfide. The kinetics of U(VI) reduction was found to be largely controlled by [CO32-]T (examined from 0.0 to 30.0 mM) and pH (examined from 6.37 to 9.06). The reduction was almost completely inhibited with the following [CO32-]T and pH combinations: [(> or = 15.0 mM, pH 6.89); (> or = 4.0 mM, pH 8.01); and (> or = 2.0 mM, pH 9.06)]. By comparing the experimental results with the calculated speciation of U(VI), it was found that there was a strong correlation between the measured initial reaction rates and the calculated total concentrations of uranium-hydroxyl species; we, therefore, concluded that uranium-hydroxyl species were the ones being reduced by sulfide, not the dominant U-carbonate species present in many carbonate-containing systems.
The transport of retinoic acid in plasma was examined in vitamin A-deficient rats maintained on small doses of radioactively labelled retinoic acid. After ultracentrifugation of serum adjusted to density 1.21, most of the radioactivity (83%) was associated with the proteins of density greater than 1.21, and not with the serum lipoproteins. Gel filtration of the labelled serum on Sephadex G-200 showed that the radioactive label was associated with protein in the molecular-weight range of serum albumin. On polyacrylamide-gel electrophoresis almost all of the recovered radioactivity migrated with serum albumin. Similar esults were obtained with serum from a normal control rat given a single oral dose of [(14)C]retinoic acid. These findings indicate that retinoic acid is transported in rat serum bound to serum albumin, and not by retinol-binding protein (the specific transport protein for plasma retinol). Several tissues and the entire remaining carcase of each rat were extracted with ethanol-acetone to determine the tissue distribution of retinoic acid and some of its metabolites. The total recover of radioactive compounds in in the entire body of the rat was about 7-9mug, representing less than 5% or 10% respectively of the total administered label in the two dosage groups studied. The results confirm that retinoic acid is not stored in any tissue. Most of the radioactive material was found in the carcase, rather than in the specific tissues analysed. Two-thirds of the radioactivity in the carcase appeared to represent unchanged retinoic acid. Of the tissues examined, the liver, kidneys and intestine had relatively high concentrations of radioactive compounds, whereas the testes and fat-pads had the lowest concentrations.
The effects of 3,4-dihydroxybutyl-1-phosphonate, a four-carbon analog of sn-glycerol 3-phosphate, on the biosynthesis of the glyceryl moiety in murein lipoprotein of Escherichia coli were studied. The compound at a concentration of 55 microM strong inhibits in the incorporation of [2-3H]glycerol radioactivity into lipoprotein by virtue of its inhibition of the synthesis of phosphatidylglycerol. On the other hand, the incorporation of prelabeled [2-3H]glycerol radioactivity into lipoprotein was only partially inhbited by 3,4-dihydroxybutyl-1-phosphonate even at a much higher concentration (1 mM). These data were consistent with the postulated pathway for the biosynthesis of the lipid moiety in lipoportein: cysteine-lipoprotein + phosphatidylglycerol leads to glycerylcystein-lipoprotein + phosphatidic acid.
Biological treatment of 2,4,6-trinitrotoluene (TNT) in soil rarely results in complete mineralization of the parent compound. More often, the largest proportion of the TNT carbon is incorporated into the soil organic matrix. Therefore, we evaluated the stability of nonextractable residues from various bioremediation processes of 14C-TNT in soils. The extractable amounts of the residual radioactivity varied between 7 and 33% and thus the nonextractable amount between 93 and 67% (3-15% in fulvic acids, 26-46% in humic acids, and 27-44% in the humin fraction). The residue-containing soils were analyzed for the release of radioactivity after treatment by physical (freeze and thaw, grinding of soil, and steam extraction), chemical (acid rain and addition of metal complexing agent), and biological methods (addition of compost, white rot fungi, radical-generating enzymes, and germination of plants). Freeze and thaw treatment and grinding of the soil did not alter the partitioning of the label significantly. Steam extraction and acid rain extraction increased the water extractability to 11 to 29% and to 51.6% in the native TNT-contaminated soil. The addition of ethylenediamine-tetraacetate (EDTA) increased the extractability from 7 to 12%. After biological treatment, only slightly increased extractability (<10%) was observed. No increase of extractable TNT or known metabolites was observed with any of the treatments. Thus, under the treatment conditions applied in this study, the residues formed during microbial transformation of TNT may be biogenic residues with low mobilization potential and low hazardous impact.