[The appearance of intravenously administered isotope-labeled oxygen in expired air].
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Administration, Intravenous↗
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Results for “Isotope Labeling”
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[PROTEIN METABOLISM BY THE MYOMETRIUM DURING PREGNANCY. AUTORADIOGRAPHIC STUDIES WITH ISOTOPE-LABELLED AMINO ACIDS ON GRAVID RATS].
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Amino Acids↗
Ionizable isotopic labeling reagent for relative quantification of amine metabolites by mass spectrometry.
A powerful approach to relative quantification by mass spectrometry is to employ labeling reagents that target specific functional groups in molecules of interest. A quantitative comparison of two or more samples may be readily accomplished by using a chemically identical but isotopically distinct labeling reagent for each sample. The samples may then be combined, subjected to purification steps, and mass analyzed. Comparison of the signal intensities obtained from the isotopically labeled variants of the target analyte(s) provides quantitative information on their relative concentrations in the sample. In this report, we describe the synthesis and use of heavy and light isotopic forms of methyl acetimidate for the relative quantification of amine-containing species. The principal advantages of methyl acetimidate as a labeling reagent are that the reaction product is positively charged and hydrophobicity is increased, both of which enhance electrospray ionization efficiency and increase detection sensitivity. The quantitative nature of the analysis was demonstrated in model metabolomics experiments in which heavy and light labeled Arabidopsis extracts were combined in different ratios. Finally, the labeling strategy was employed to determine differences in the amounts of amine-containing metabolites for Arabidopsis seeds germinated under two different conditions.
Amines↗
Does a stable isotopically labeled internal standard always correct analyte response? A matrix effect study on a LC/MS/MS method for the determination of carvedilol enantiomers in human plasma.
A stable isotopically labeled (SIL) analogue is believed to be the most appropriate internal standard in a quantitative bioanalytical liquid chromatography/tandem mass spectrometry (LC/MS/MS) assay. It is assumed that a SIL internal standard always compensates for variability in chemical derivatization, sample extraction and LC/MS/MS analysis due to its nearly identical chemical and physical properties to the unlabeled analyte. Hence, the analyte to internal standard peak area ratio should be constant despite any variations in sample processing or analysis. However, in our laboratories, a deuterium labeled internal standard of carvedilol demonstrated an unexpected behavior-the analyte to internal standard peak area ratio changed with two specific lots of commercially supplied human plasma. Several experiments, including dilution of the extract with LC mobile phase and post-column infusion of the carvedilol solution followed by the injection of extracted blank plasma, have indicated that a high level of matrix suppression affected the ionization of the carvedilol-S enantiomer and its deuterated internal standard differently in these two lots of plasma. For the first time, it was clearly demonstrated that a slight difference in retention time between the analyte and the SIL internal standard, caused by deuterium isotope effect, has resulted in a different degree of ion suppression between these two analogues. This difference was significant enough to change the analyte to internal standard peak area ratio and affect the accuracy of the method.
Adrenergic Antagonists↗
Switching from an analogous to a stable isotopically labeled internal standard for the LC-MS/MS quantitation of the novel anticancer drug Kahalalide F significantly improves assay performance.
The importance of a stable isotopically labeled (SIL) internal standard for the quantitative LC-MS/MS assay for Kahalalide F in human plasma is highlighted. Similar results can be expected for other LC-MS/MS assays. Therefore, we emphasize the need for an SIL internal standard for accurate and precise LC-MS/MS assays of drugs in biological matrices.
Antineoplastic Agents↗
The use of isotope-labelled red cells to study incompatibility.
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Blood Transfusion↗
Simultaneous quantitative estimates of several isotopically labelled substances in the picogram range with selected ion monitoring.
The use of a model developed by the authors for the simultaneous quantitative determination of several isotopically labelled substances of the same chemical structure is described in detail for a two substance system. A computational flow chart is included. An example using natural estradiol and 4-[14C] labelled estradiol with manifold deuterated estradiol as an internal standard is presented. The basis of the model is discussed.
Chromatography, Gas↗
Thermal isomerizations of 1-(13)c-2,2,3,3-d(4)-cyclopropane to isotopically labeled trimethylene diradicals, 1-propylidenes, and propenes.
The gas-phase thermal isomerizations of 1-13C-2,2,3,3-d4-cyclopropane lead to isotopically labeled propenes characteristic of both the traditional reaction mechanism involving a trimethylene diradical intermediate and a previously predicted, but never observed, path involving rate-limiting conversion of the cyclopropane to singlet 1-propylidenes, followed by a [1,2]-deuterium shift. The isomerizations give mixtures of both 1-13C-2,3,3,3-d4-propene and 1-13C-1,2,3,3-d4-propene, products characteristic of the two mechanisms that are clearly observable by 13C{1H} NMR spectroscopy.
Journal Article↗
Intracellular compartmentation in the biosynthesis of caulerpenyne: study on intact macroalgae using stable-isotope-labeled precursors.
The biosynthesis of caulerpenyne 1 was studied in the invasive green alga Caulerpa taxifolia. The investigation was performed on intact algae with stable-isotope-labeled precursors administered under mixotrophic growth conditions. According to the labeling pattern, after incorporation of 1-(13)C-acetate and (13)CO(2), respectively, the biosynthesis of the sesquiterpene backbone occurs in the chloroplast and follows the methyl-erythritol-4-phosphate (MEP) pathway. In contrast, the acetyl residues of caulerpenyne 1 are derived from a cytosolic resource. [structure: see text]
Journal Article↗
Use of isotope-labeled somatostatin analogs for visualization of islet cell tumors.
The results of visualization of the islet cell tumors of 25 patients after intravenous administration of two isotope-labeled somatostatin analogs (123I-Tyr3-octreotide and 111In-octreotide) are described. The primary tumors, as well as previously often unrecognized distant metastases were visualized in 20 of the 25 patients (80%). Parallel in vitro detection of somatostatin receptors on those tumors that had also been visualized in vivo indicates that the ligand binding to the tumor in vivo indeed represents binding to specific somatostatin receptors. The detection of somatostatin receptors on these tumors in vivo predicted a good suppressive effect of octreotide on hormonal hypersecretion by these tumors. It is an easy, quick, harmless procedure that is valuable for localization of primary endocrine pancreatic tumors and their often radiologically and clinically not yet recognized metastases.
Adenoma, Islet Cell↗
The effect of pregnancy in humans on the pharmacokinetics of stable isotope labelled phenytoin.
1. To investigate the mechanism of the fall in steady-state plasma phenytoin concentration relative to drug dose that occurs during pregnancy, single dose pharmacokinetic studies with stable isotope labelled phenytoin were carried out at different stages of pregnancy, and 2 to 4 months post-natally, in five epileptic women receiving regular oral therapy with the drug. 2. Steady-state apparent plasma clearances of phenytoin (dose/steady-state concentration) correlated closely with simultaneous plasma clearances of the intravenous stable-isotope drug (measured as dose/AUC) suggesting that the patients were complaint with therapy when their phenytoin dosage requirement increased during the pregnancy, and that the oral drug was fully bioavailable. 3. In retrospect, two of the five subjects were probably studied too early post-natally for phenytoin elimination kinetics to have returned to non-pregnant values. Despite this, (i) the mean +/- s.d. t 1/2 for phenytoin was statistically significantly shorter in pregnancy than post-natally (31 +/- 14 vs 39 +/- 28 h), (ii) the mean +/- s.d. whole plasma clearance was also statistically significant greater (0.025 +/- 0.012 vs 0.021 +/- 0.013 kg-1 h-1) and (iii) the mean +/- s.d. Vmax for phenytoin elimination was statistically significantly greater in pregnancy (1170 +/- 600 mg day-1) than post-natally (780 +/- 470 mg day-1). Although the mean +/- s.d. apparent Km was higher in pregnancy (18.2 +/- 8.4 mg l-1, expressed in terms of whole plasma drug concentrations, compared with 10.2 +/- 7.4 mg l-1 post-natally), the difference was not statistically significant. However, if the apparent Km value was expressed in terms of plasma water phenytoin concentrations the difference (pregnant 2.50 +/- 0.85 mg l-1: post-natally 1.16 +/- 0.65 mg l-1) was statistically significant. 4. Human pregnancy appears to result in an increased capacity to eliminate phenytoin.
Adult↗
Offset profiles of selective pulses in isotopically labeled macromolecules.
The experimental verification of offset profiles and calibration of selective pulses in NMR is usually carried out with doped water samples but not under conditions typical of macromolecules with short T2, long T1, and possibly homo- and heteronuclear couplings. A new method for selective excitation in isotopically labeled macromolecules is shown to be particularly suited to this purpose. This is illustrated for a backbone amide resonance in a sample of 15N-labeled human ubiquitin.
Amides↗
Chemical ligation of folded recombinant proteins: segmental isotopic labeling of domains for NMR studies.
A convenient in vitro chemical ligation strategy has been developed that allows folded recombinant proteins to be joined together. This strategy permits segmental, selective isotopic labeling of the product. The src homology type 3 and 2 domains (SH3 and SH2) of Abelson protein tyrosine kinase, which constitute the regulatory apparatus of the protein, were individually prepared in reactive forms that can be ligated together under normal protein-folding conditions to form a normal peptide bond at the ligation junction. This strategy was used to prepare NMR sample quantities of the Abelson protein tyrosine kinase-SH(32) domain pair, in which only one of the domains was labeled with 15N. Mass spectrometry and NMR analyses were used to confirm the structure of the ligated protein, which was also shown to have appropriate ligand-binding properties. The ability to prepare recombinant proteins with selectively labeled segments having a single-site mutation, by using a combination of expression of fusion proteins and chemical ligation in vitro, will increase the size limits for protein structural determination in solution with NMR methods. In vitro chemical ligation of expressed protein domains will also provide a combinatorial approach to the synthesis of linked protein domains.
Amino Acid Sequence↗
Evidence for light-induced 13-cis, 14-s-cis isomerization in bacteriorhodopsin obtained by FTIR difference spectroscopy using isotopically labelled retinals.
We have obtained by Fourier transformed infra-red (FTIR)-spectroscopy BR-K, BR-L and BR-M difference spectra of bacteriorhodopsin regenerated with isotopically labelled retinals. Thereby, we are able to assign reliably the C(14)-C(15) and C=N stretching vibrations of the various intermediates. The lower C(14)-C(15) stretching vibration frequency in L as compared with 13-cis protonated Schiff base model compounds indicates a 13-cis, 14-s-cis configuration of the retinal in this species. The unusually low C=N stretching vibration in K at 1615 cm indicates less stabilization of the positive charge at the Schiff base by the protein environment. Based on these results, a mechanism is suggested by which the stored light energy is transformed into proton transfers.
Journal Article↗
Bioavailability of imipramine tablets relative to a stable isotope-labeled internal standard: increasing the power of bioavailability tests.
A new methodology for comparative bioavailability testing is described in which each drug formulation is compared with a stable isotope-labeled variant of the drug that is consumed orally in solution at the same time the tested formulation is ingested. The methodology is used to determine the comparative bioavailabilities of two commercially available brands of imipramine hydrochloride. The power of the new methodology to detect differences between drug formulations, when, in fact, such differences exist, is shown to be superior to that of conventional bioavailability tests.
Adolescent↗
Assay of stable isotope labelled urea in biological fluids by selected ion monitoring.
A selected ion-monitoring method, incorporating an internal standard, was developed to allow the direct and simultaneous measurement of stable isotope-labelled urea and unlabelled urea concentrations in biological specimens. After cyclization of urea with malonaldehyde bis(dimethylacetal) to form 2-hydroxypyrimidine, the volatile heptafluorobutyryl derivative was made in a two-step process utilizing a trimethylsilyl intermediate. The internal standard, 4-methyl-2-hydroxypyrimidine, was found to be stable under the cyclization conditions. The structures of the internal standard and urea derivatives were confirmed by electron impact and chemical ionization mass spectrometry. This method was applied to the measurement of [15N2]urea concentrations in dog plasma.
Body Fluids↗
Quantitation of cortisol and related 3-oxo-4-ene steroids in urine using gas chromatography/mass spectrometry with stable isotope-labeled internal standards.
A method for the profiling of several important 3-oxo-4-ene urinary steroids is reported. The methodology is combined gas chromatography/mass spectrometry (GC/MS) utilizing stable isotope-labeled internal standards. The following standards were obtained or easily synthesized: [9, 11, 12, 12-2H4]cortisol, [1,2-2H2] and [9, 12, 12-2H2]cortisone, [1,2-2H2]6 beta-hydroxycortisol, and [1,2-2H2]18-hydroxycortisol. We found the following excretions of free steroids for normal adult males and females: cortisol (males mean +/- SD, 35 +/- 13; females mean +/- SD, 23 +/- 13), cortisone (males mean +/- SD, 58 +/- 23; females mean +/- SD, 50 +/- 22), 6 beta-hydroxycortisol (males mean +/- SD, 164 +/- 59; females mean +/- SD, 108 +/- 55), and 18-hydroxycortisol (males mean +/- SD, 148 +/- 55; females mean +/- SD, 71 +/- 30). For 18-hydroxycortisol in particular, the excretions were much higher for males than for females. We found that the larger part of urinary cortisol and cortisone is not free but is released from conjugation by enzymes present in snail digestive juice. Using a pooled urine sample from an equal number of male and female subjects, we found that for cortisol 29% was excreted free, 28% as glucuronide and 43% as other conjugates (probably sulfates). For cortisone 41% was free, 45% beta-glucuronide and 14% as other conjugates. Relatively little (3-8%) of the hydroxylated cortisols were excreted conjugated.
Adolescent↗
Recent developments in solid-state magic-angle spinning, nuclear magnetic resonance of fully and significantly isotopically labelled peptides and proteins.
In recent years, a large number of solid-state nuclear magnetic resonance (NMR) techniques have been developed and applied to the study of fully or significantly isotopically labelled ((13)C, (15)N or (13)C/(15)N) biomolecules. In the past few years, the first structures of (13)C/(15)N-labelled peptides, Gly-Ile and Met-Leu-Phe, and a protein, Src-homology 3 domain, were solved using magic-angle spinning NMR, without recourse to any structural information obtained from other methods. This progress has been made possible by the development of NMR experiments to assign solid-state spectra and experiments to extract distance and orientational information. Another key aspect to the success of solid-state NMR is the advances made in sample preparation. These improvements will be reviewed in this contribution. Future prospects for the application of solid-state NMR to interesting biological questions will also briefly be discussed.
Capsid Proteins↗