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The carbon-14-labeled carbon dioxide that is released by respiration after glucose labeled with carbon-14 is applied to fungal mycelium can be reabsorbed in highly significant amounts by distant mycelium and agar media in the same petri dishes. Atmospheric transfer of carbon-14 must be considered when using labeled organic compounds to study translocation in fungi.
This paper presents an aerosol generation technique developed to produce dry aerosol particles of various sizes from aqueous solutions of salt. The technique was tested with sodium chloride, lithium carbonate and uranyl acetate at various aqueous concentrations which produced particles in the size range of 0.13-1.37 microm Mass Median Diameter (MMD). The generated aerosols were acceptably monodisperse with a geometric standard deviation of 1.4-2. Both MMD and Mass Median Aerodynamic Diameter (MMAD) increased significantly (p<0.001) with increased concentration of the salt in solution. The technique can also be used to generate aerosols of different chemical species. The results obtained indicate that the system is convenient for use with various aerosol-forming materials, with a stable particle size distribution being maintained for a long period of steady operation. The technique was successfully applied in wind tunnel studies to simulate the release of submicron radioactive particles and their interception by crops, grass and tree canopies. The relevance and application of the technique in other areas of environmental assessment studies is discussed.
1. The effect of the absence of oxygen on the metabolism of [U-(14)C]glucose by the rabbit lens has been examined. 2. Protein-free extracts of incubated lens were subjected to electrophoresis followed by chromatography on paper; radioautographs showed 10 compounds substantially labelled. In the absence of oxygen, less radioactivity appeared in glucose, sorbitol, fructose, alanine, glutamic acid, glutathione and nucleotides, and more in lactic acid, alpha-glycerophosphate and glycerol. 3. The radioactivity of lens protein was about two to four times greater after aerobic than after anaerobic incubation. 4. The radioactivity of carbon dioxide was 2- to 4-fold greater after aerobic incubation than after anaerobic incubation. 5. After aerobic incubation of the lens, the radioactivity of all the labelled compounds was higher in the outer part (cortex) than in the inner part (nucleus). 6. Free glycerol has been found to be present in the lens. Its concentration, and that of alpha-glycerophosphate, has been measured in the lens of several species of animal.
The tricyclic carboxamide N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) is a DNA-intercalating agent capable of inhibiting both topoisomerases I and II and is currently in Phase II clinical trial. Many related analogues have been developed, but despite their potent in vitro cytotoxicities, they exhibit poor extravascular distribution. As part of an ongoing drug development program to obtain related "minimal intercalators" with lower DNA association constants, we have compared the biodistribution and metabolite profiles of the prototype compound, DACA, with three analogues to aid rational drug selection. All of these compounds share a common structural feature, N-dimethyl side chain, which was radiolabeled with the positron-emitting radioisotope, carbon-11. This strategy was selected because it allows promising candidates emerging from preclinical studies in animals to be evaluated rapidly in humans using positron emission tomography (PET). The acridine DACA, the phenazine SN 23490, the pyridoquinoline SN 23719, and the dibenzodioxin SN 23935 were found to be cytotoxic in in vitro assays with an IC50 of 1.4-1.8 microM, 0.4-0.6 microM, 1.3-1.6 microM, and 24-36 microM, respectively, in HT29, U87MG, and A375M cell lines. Ex vivo biodistribution studies with carbon-11 radiolabeled compounds in mice bearing human tumor xenografts showed rapid clearance of 11C-radioactivity (parent drug and metabolites) from blood and the major organs. Rapid hepatobiliary clearance and renal excretion were also observed. There was low [<5% of injected dose/gram (%ID/g)] and variable uptake of 11C-radioactivity in three tumor types for all of the compounds. Tumor (U87MG) to blood 11C-radioactivity for [11C]DACA, [11C](9-methoxyphenazine-1-carboxamide (SN 23490), [11C]2-(4-pyridyl)quinoline-8-carboxamide (SN 23719), and [11C]dibenzo[1,4]dioxin-1-carboxamide (SN 23935) at 30 min were 2.9 +/- 1.1, 2.3 +/- 0.6, 2.6 +/- 0.6, and 0.7 +/- 0.2, respectively. For SN 23719, the distribution of 11C-radioactivity in normal tissues and tumors determined ex vivo was in broad agreement with that determined in vivo by whole body PET scanning. [11C]DACA was rapidly and extensively metabolized to several plasma metabolites and a major tumor metabolite. In contrast, [11C]SN 23935, [11C]SN 23490, and [11C]SN 23719 showed less extensive metabolism. In the tumor samples, the parent [11C]DACA and [11C]SN 23935 represented between 0.3 and 1.5%ID/g, whereas [11C]SN 23490 and [11C]SN 23719 represented between 1.5 and 2.8%ID/g. In conclusion, by using a strategy with 11C-labeling, we have determined the tissue distribution and metabolic stability of novel tricyclic carboxamides with the view of selecting analogues with potentially better in vivo activity against solid tumors. SN 23490 and SN 23719 had more favorable distribution and metabolic stability compared with DACA and SN 23935 and may warrant further development. The radiolabeling strategy used allows ex vivo and in vivo evaluation of promising anticancer agents in animals and offers the potential of rapid translation to studies in humans using PET.
The concentrations of several toxic heavy metals and volatile organic compounds (VOCs) in various types of Hungarian fly-ash fine particulates were investigated by means of instrumental neutron activation analysis, X-ray fluorescence analysis and gas chromatography, coupled with mass spectrometry. Within a power station, particulate samples were taken from the boiler zone (BO), from the electrostatic dust filter chamber (FI) and from the flue-gas at the top of the stack (ST). Enrichment rates of the toxic metals both in FI and ST particulate fractions related to the BO concentrations were calculated to enable the temperature dependence on the adsorption of the toxic components to be studied. In addition, both the total amounts of the VOCs and their partial distributions in accordance with the number of carbon atoms were also studied in fly-ash particulates. From them, 31 organic species were identified and determined. Since Hungarian brown coals have high uranium and thorium contents, the specific radioactivities of the daughter isotopes of both the 232Th and 238U decay series were also measured and are discussed.
The systemic plasma pharmacokinetics of genistein were determined in rats to evaluate the absolute oral bioavailability and make comparison with similar data in the literature derived from humans subjects. The plasma concentrations of genistein, genistein glucuronide and carbon-14 were determined by LC-MS/MS and liquid scintillation counting following oral and intravenous dosing with [14C]genistein (4 mg kg(-1) body weight). The absorption of total radioactivity from the gut, (parent compound and metabolites), was 56 and 111% in male and female rats, respectively. In contrast, the absolute oral bioavailability of genistein in male and female rats was 7 and 15%. There was a significant (P<0.001) difference between Cmax of genistein after intravenous (6921 and 4392 ng/ml) and oral (21 and 22 ng/ml) dosing in male and female rats, respectively. After oral administration, the concentration profile of genistein glucuronide in plasma greatly exceeded that of parent compound during the absorption/distribution phase suggesting extensive first pass metabolism, and provided evidence of entero-hepatic circulation. Selective plasma analysis by LC-MS/MS, without prior enzymatic hydrolysis, enabled ready discrimination between parent and conjugated metabolites and prevented gross overestimation of genistein bioavailability. Pharmacokinetic parameters Cmax, Tmax and AUC were similar to those reported in humans, which supports the use of the rat model for genistein toxicity studies.
The metabolism of D- and L-pipecolic acid has been investigated in rabbits and rats. A rapid evolution of 14CO2 followed the injection of either D- or L-pipe[6-14C]colic acid into rabbits. Rabbit kidney slices degraded to CO2 both isomers of lysine and of pipecolic acid. Rabbit liver was effective with only the L-isomers. In the rat, very little of injected L-pipecolic acid was catabolized to CO2, and large amounts were excreted unchanged into the urine, L-Lysine was efficiently metabolized to CO2 by rat liver and kidney slices but not D-lysine or either isomer of pipecolic acid. Rat kidney converted D-lysine to L-pipecolic acid. The L-isomer was identified by co-precipitation of the radioactive product with authentic compounds.
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Halofenate-free acid (HFA) inhibited the growth of Saccharomyces cerevisiae by 50% at a concentration of 0.34 mm. This inhibitory effect was prevented by addition of either oleate or acetate, but not by pyruvate. When cell growth was supported by oleate, HFA inhibited the incorporation of radioactive carbon from glucose-U-(14)C or pyruvate-2-(14)C into fatty acids and sterols. The incorporation of radioactive carbon into fatty acids and sterols from acetate-2-(14)C was unaffected by the compound. When cell growth was supported by either oleate or acetate, HFA inhibited the conversion of pyruvate-1-(14)C to (14)CO(2). These results suggest that HFA inhibits the conversion of pyruvate to acetate in yeast. Partially purified yeast pyruvate dehydrogenase was inhibited 50% by 5.5 mm HFA; however, the concentration required for 50% inhibition was considerably reduced when the enzyme was preincubated with the compound at room temperature. In a similar manner, the hypolipidemic agent clofibrate-free acid inhibited the growth of yeast by 50% at 3.0 mm. This inhibition was also prevented by acetate and not by pyruvate. In addition, clofibrate-free acid inhibited partially purified pyruvate dehydrogenase by 50% at a concentration of 37.0 mm.
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Incorporation of radioactivity from intracranially injected radioactive leucine, isoleucine (ketogenic amino acids), octanoic acid and beta-hydroxybutyric acid into the brain lipids of 15 to 16 day-old rats was examined. The results showed that radioactivity from all the above precursors was incorporated into brain lipids. Radioactivity from injected isoleucine was incorporated into odd numbered fatty acids indicating an alternate pathway to alpha-oxidation for the biosynthesis of these fatty acids in the brain. For some as yet unclear reasons, a substantial portion of the radioactivity from injected octanoic acid was incorporated into free fatty acids. Utilization of these compounds for providing carbon for lipogenesis during development under unstressed normal conditions is discussed.
The metabolism of 2-amino-3-phosphono-[2-(14)C]propionic acid or 2-amino-3-phosphono-[3-(14)C]propionic acid in rats was studied in vivo and in vitro. The radioactivity in expired CO2 from the [3-(14)C]-labelled compound indicated the cleavage of the carbon-phosphorus (C-P) bond. A small amount of the [2-(14)C]-labelled compound and the [3-(14C]-labelled compound was incorporated into 2-aminoethylphosphonic acid, and polar lipid of the liver and kidney contained the 2-aminoethylphosphonic acid. The 2-amino-3-phosphonopropionic acid was not detected at the lipid level. Incorporation of the [3-(14)C]-labelled compound into a variety of metabolites including 3-phosphonopyruvic acid and 2-phosphonoacetaldehyde suggests the transamination reaction as a decomposition mechanism of 2-amino-3-phosphonopropionic acid in mammals.
The toxicity of the insecticide, lindane, was measured in the midge, Chironomus riparius, at pH 4, 6, and 8 with the finding that lindane is significantly more toxic at pH 6 than at pH 4 and 8. The higher toxicity of lindane at pH 6 is a product of two factors. First the penetration of the compound into the midge is lower at pH 4 than at pH 6 and 8. Second, a greater percentage of total radioactivity is contributed by parent compound at pH 6.
Immobilization of the high-level nuclear waste stored at the Hanford Reservation has been complicated by the presence of soluble, lower-valent technetium species. Previous work by Schroeder and Blanchard has shown that these species cannot be removed by ion-exchange and are difficult to oxidize. The Tc K-edge XANES spectra of the species in Tanks SY-101 and SY-103 were reported by Blanchard, but they could not be assigned to any known technetium complex. We report that the XANES spectra are most likely those of Tc(I)-carbonyl species, especially fac-Tc(CO)3(gluconate)(2-). This is further supported by EXAFS and 99Tc-NMR studies in nonradioactive simulants of these tank wastes.
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We have studied by tracer technique the interconversion of the carbon skeleton of alanine with that of glucose. The data analysis is in terms of renewal theory rather than traditional compartmental analysis. This eliminates the need for estimation of compartment size, which is particularly difficult to determine in the case of alanine. In addition, the conversion rates between the two substances are found by considering the two components which are responsible for the determined radioactivity curves, namely, the first conversion of the labeled carbon and its subsequent movement in the product compound. The subjects of the study were for the most part underweight but had been hospitalized and eating a standard hospital diet for at least 3 days prior to the studies. Our data indicate that nearly twice as much carbon from glucose is cycled to alanine as is recycled from alanine back to glucose after a 14 hr overnight fast. Small amounts of glucose suppress the alanine-glucose arm of the cycle but probably do not change the glucose-alanine conversion. The contribution of glucose carbon to alanine metabolism is significant and appears to be immediately influenced by the magnitude of glycolysis.
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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 .