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PubMedDate not supplied

Low kinetic hydrogen isotope effects in the dehydrogenation of 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid dimethyl ester (nifedipine) by cytochrome P-450 enzymes are consistent with an electron/proton/electron transfer mechanism.

Cytochrome P-450 enzymes have been postulated to oxidize amines through a variety of mechanisms. One of the means of distinguishing among potential pathways involves the use of kinetic hydrogen isotope effects: low isotope effects are characteristic of aminium radical mechanisms while high values are consistent with hydrogen atom abstraction, a process documented in alkane hydroxylation. Nifedipine [1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic+ ++ acid dimethyl ester] was prepared with isotopic substitution at the 4-position and utilized in determinations of the deuterium and tritium kinetic isotope effects. The noncompetitive intermolecular deuterium [DV, D(V/K)] and competitive intermolecular tritium [T(V/K)] isotope effects observed in the oxidation of nifedipine with liver microsomes prepared from untreated male rats were less than 2. Similar low deuterium and tritium isotope effects (less than 2) were also found with six other types of rat liver microsomal preparations and with three different human liver microsomal preparations, even though the rates of oxidation (expressed per nanomole of total cytochrome P-450) varied by an order of magnitude and other investigations indicate that several different cytochrome P-450 enzymes can catalyze the reaction. Similar low deuterium and tritium isotope effects were measured with a purified rat liver cytochrome P-450 preparation and horseradish peroxidase. These results are interpreted in terms of an electron/proton/electron transfer mechanism previously postulated for the oxidation of other dihydropyridines by cytochrome P-450 enzymes and model one-electron acceptors and argue against a mechanism involving hydrogen atom abstraction from nifedipine.

Animals↗
PubMed2001

Decarboxylation of glycine contributes to carbon isotope fractionation in photosynthetic organisms.

Carbon isotope effects were investigated for the reaction catalyzed by the glycine decarboxylase complex (GDC; EC 2.1.2.10). Mitochondria isolated from leaves of pea (Pisum sativum L.) and spinach (Spinacia oleracea L.) were incubated with glycine, and the CO(2) evolved was analyzed for the carbon isotope ratio (delta(13)C). Within the range of parameters tested (temperature, pH, combination of cofactors NAD(+), ADP, pyridoxal 5-phosphate), carbon isotope shifts of CO(2) relative to the C(1)-carboxyl carbon of glycine varied from +14 per thousand to -7 per thousand. The maximum effect of cofactors was observed for NAD(+), the removal of which resulted in a strong (12)C enrichment of the CO(2) evolved. This indicates the possibility of isotope effects with both positive and negative signs in the GDC reaction. The measurement of delta(13)C in the leaves of the GDC-deficient barley (Hordeum vulgare L.) mutant (LaPr 87/30) plants indicated that photorespiratory carbon isotope fractionation, opposite in sign when compared to the carbon isotope effect during CO(2) photoassimilation, takes place in vivo. Thus the key reaction of photorespiration catalyzed by GDC, together with the key reaction of CO(2) fixation catalyzed by ribulose-1,5-bisphosphate carboxylase, both contribute to carbon isotope fractionation in photosynthesis.

Journal Article↗
PubMed2003

Efficient mixing of the solar nebula from uniform Mo isotopic composition of meteorites.

The abundances of elements and their isotopes in our Galaxy show wide variations, reflecting different nucleosynthetic processes in stars and the effects of Galactic evolution. These variations contrast with the uniformity of stable isotope abundances for many elements in the Solar System, which implies that processes efficiently homogenized dust and gas from different stellar sources within the young solar nebula. However, isotopic heterogeneity has been recognized on the subcentimetre scale in primitive meteorites, indicating that these preserve a compositional memory of their stellar sources. Small differences in the abundance of stable molybdenum isotopes in bulk rocks of some primitive and differentiated meteorites, relative to terrestrial Mo, suggest large-scale Mo isotopic heterogeneity between some inner Solar System bodies, which implies physical conditions that did not permit efficient mixing of gas and dust. Here we report Mo isotopic data for bulk samples of primitive and differentiated meteorites that show no resolvable deviations from terrestrial Mo. This suggests efficient mixing of gas and dust in the solar nebula at least to 3 au from the Sun, possibly induced by magnetohydrodynamic instabilities. These mixing processes must have occurred before isotopic fractionation of gas-phase elements and volatility-controlled chemical fractionations were established.

Journal Article↗
PubMed2004

Osmium isotopic constraints on the nature of the DUPAL anomaly from Indian mid-ocean-ridge basalts.

The isotopic compositions of mid-ocean-ridge basalts (MORB) from the Indian Ocean have led to the identification of a large-scale isotopic anomaly relative to Pacific and Atlantic ocean MORB. Constraining the origin of this so-called DUPAL anomaly may lead to a better understanding of the genesis of upper-mantle heterogeneity. Previous isotopic studies have proposed recycling of ancient subcontinental lithospheric mantle or sediments with oceanic crust to be responsible for the DUPAL signature. Here we report Os, Pb, Sr and Nd isotopic compositions of Indian MORB from the Central Indian ridge, the Rodriguez triple junction and the South West Indian ridge. All measured samples have higher (187)Os/(188)Os ratios than the depleted upper-mantle value and Pb, Sr and Nd isotopic compositions that imply the involvement of at least two distinct enriched components in the Indian upper-mantle. Using isotopic and geodynamical arguments, we reject both subcontinental lithospheric mantle and recycled sediments with oceanic crust as the cause of the DUPAL anomaly. Instead, we argue that delamination of lower continental crust may explain the DUPAL isotopic signature of Indian MORB.

Journal Article↗
PubMed2001

Determination of Ba, Cd, Cu, Pb and Zn in saliva by isotope dilution direct injection inductively coupled plasma mass spectrometry.

Trace elements in small sample volumes of saliva were determined by coupling a high efficiency direct injection nebulizer to inductively coupled plasma mass spectrometry and employing quantification by isotope dilution. Aliquots of 0.4 ml of human saliva were mixed with 0.1 ml of concentrated nitric acid and diluted to 2 ml with water. Sample solutions were spiked with an isotopic solution enriched in 135Ba, 112Cd, 65Cu, 206Pb and 66Zn. The amount of each isotope added to the samples and the measurement procedure were adjusted to attain precise analytical results calculated from the isotope ratios 135Ba/138Ba, 112Cd/114Cd, 65Cu/63Cu, 206Pb/208Pb and 66Zn/68Zn. Data acquisition for Ba, Cu and Zn isotopes was performed for a single sample injection of 50 microl and in another sample injection the Cd and Pb isotopes were measured. Concentrations ranging from 5.0 to 16 microg l(-1) for Ba, from 0.50 to 1.1 microg l(-1) for Cd, from 6.0 to 50 microg l(-1) for Cu, from 0.8 to 18.8 microg l(-1) for Pb and from 46.0 to 230 microg l(-1) for Zn were found in saliva samples. Detection limits of 0.11, 0.03, 0.40, 0.05 and 0.59 microg l(-1) were determined for Ba, Cd, Cu, Pb and Zn, respectively. The concentrations found by isotope dilution were in agreement with those of the completely digested samples quantified by external calibration. The direct analysis of 30 samples per hour was attained with the proposed procedure, avoiding time-consuming digestion steps, contamination risks and matrix effects.

Barium↗
PubMed2004

Mass-independent isotope effect in the earliest processed solids in the solar system: a possible chemical mechanism.

A major constraint is described for a possible chemical origin for the "mass-independent" oxygen isotope phenomenon in calcium-aluminum rich inclusions (CAIs) in meteorites at high temperatures ( approximately 1500-2000 K). A symmetry-based dynamical eta effect is postulated for O atom-monoxide recombination on the surface of growing CAIs. It is the surface analog of the volume-based eta effect occurring in a similar phenomenon for ozone in the gas phase [Y. Q. Gao, W. C. Chen, and R. A. Marcus, J. Chem. Phys. 117, 1536 (2002), and references cited therein]: In the growth of CAI grains an equilibrium is postulated between adsorbed species XO (ads)+O (ads) <==>XO*(2)(ads), where XO*(2)(ads) is a vibrationally excited adsorbed dioxide molecule and X can be Si, Al, Ti, or other metals and can be C for minerals less refractory than the CAIs. The surface of a growing grain has an entropic effect of many order of magnitude on the position of this monoxide-dioxide equilibrium relative to its volume-based position by acting as a concentrator. The volume-based eta effect for ozone in the earlier study is not applicable to gas phase precursors of CAIs, due to the rarity of three-body recombination collisions at very low pressures and because of the high H(2) and H concentration in solar gas, which reduces gaseous O and gaseous dioxides and prevents the latter from acting as storage reservoirs for the two heavier oxygen isotopes. A surface eta effect yields XO*(2)(ads) that is mass-independently rich in (17)O and (18)O, and yields XO (ads)+O (ads) that is mass-independently poor in the two heavier oxygen isotopes. When the XO*(2)(ads) is deactivated by vibrational energy loss to the grain, it has only one subsequent fate, evaporation, and so undergoes no further isotopic fractionation. After evaporation the XO(2) again has only one fate, which is to react rapidly with H and ultimately form (16)O-poor H(2)O. The other species, O (ads)+XO (ads), are (16)O rich and react with Ca (ads) and other adsorbed metal atoms or metallic monoxides to form CAIs. The latter are thereby mass-independently poor in (17)O and (18)O. Some O (ads) used to form the minerals are necessarily in excess of the XO (ads), because of the stoichiometry of the mineral, and modify the fractionation pattern. This effect is incorporated into the mechanistic and mathematical scheme. A merit of this chemical mechanism for the oxygen isotope anomaly is that only one oxygen reservoir is required in the solar nebula. It also does not require a sequestering of intermediate products which could undergo isotopic exchange, hence undoing the original isotopic fractionations. The gas phase source of adsorbed O atoms in this environment is either O or H(2)O. As inferred from data on the evaporation of Mg(2)SiO(4) taken as an example, the source of O (ads) is primarily H(2)O rather than O and is accompanied by the evolution of H(2). Nonisotopic kinetic experiments can determine more sharply the mechanism of condensed phase growth of these minerals. Laboratory tests are proposed to test the existence of a surface eta effect on the growing CAI surfaces at these high temperatures.

Journal Article↗
PubMed1985

Can a sponge fractionate isotopes?

The study has unequivocally demonstrated that siliceous sponges Spirastrella cuspidifera and Prostylyssa foetida from the same microecological niche exhibit a high degree of species specificity, while accumulating a host of heavy metal ions (Ni, Cr, Cd, Sn, Ti, Mo, Zr). S. cuspidifera accumulated, in addition, 60Co and 63Ni, showing discrimination against other radionuclides, 137Cs and 131I, present in the ambient waters receiving controlled low level waste discharges from a B.W.R. nuclear power station. P. foetida, on the other hand, accumulated only 131I and showed discrimination against other radionuclides including 60Co, although the stable iodine concentrations in both the sponges were the same. The specific activity of 60Co (in becquerels per gram of 59Co) in S. cuspidifera and 131I (in becquerels per gram of 127I) in P. foetida were at least two orders of magnitude greater than in the ambient sea water. That of 63Ni (in becquerels per gram of 62Ni) in S. cuspidifera, on the other hand, was lower by two orders of magnitude than in either abiotic matrices from the same environment. Thus, not only did both the species show bioaccumulation of a specific element, but also preferential uptake of isotopes of the same element, though they were equally available for intake. Such differential uptake of isotopes can possibly be explained in terms of two quite different mechanisms operating, each applicable in a particular case. One is that the xenobiotic isotope enters the environment in a physicochemical form or as a complex different from that of its natural counterpart. If equilibration with the latter is slow, so that the organism acquires the xenobiotic in an unfamiliar chemical context, it may treat it as a chemically distinct entity so that its concentration factor differs from that of stable isotope, thus changing the specific activity. Alternatively, if the xenobiotic is present in the same chemical form as the stable isotope, the only way in which specific activities can be modified is by fractionation on the basis of mass of isotope. In view of the remarkable concentration factors observed for stable and radioactive isotopes of the same element and the specific activities reached, it is desirable that species of sponges, especially from the coastal and estuarine environments, be monitored to detect levels of pollution due to anthropogenic substances.

Animals↗
PubMed1997

Carbon Isotopic Fractionation Does Not Occur during Dark Respiration in C3 and C4 Plants.

The magnitude of possible carbon isotopic fractionation during dark respiration was investigated with isolated mesophyll cells from mature leaves of common bean (Phaseolus vulgaris L.), a C3 plant, and corn (Zea mays L.), a C4 plant. Mesophyll protoplasts were extracted from greenhouse-grown leaves and incubated in culture solutions containing different carbohydrate substrates (fructose, glucose, and sucrose) with known [delta]13C values. The CO2 produced by protoplasts after incubation in the dark was collected, purified, and analyzed for its carbon isotope ratio. From observations of the isotope ratios of the substrate and respired CO2, we calculated the carbon isotope discrimination associated with metabolism of each of these substrates. In eight of the 10 treatment combinations, the carbon isotope ratio discrimination was not significantly different from 0. In the remaining two treatment combinations, the carbon isotope ratio discrimination was 1[per mille (thousand) sign]. From these results, we conclude that there is no significant carbon isotopic discrimination during mitochondrial dark respiration when fructase, glucose, or sucrose are used as respiratory substrates.

Journal Article↗
PubMed1980

Isotopic Fractionation Associated With Symbiotic N(2) Fixation and Uptake of NO(3) by Plants.

Isotopic fractionation associated with N(2) fixation and NO(3) (-) uptake by plants are relevant to the accuracy of estimates of N(2) fixation based on differences in the natural abundance of (15)N between N(2) fixing and nonfixing plants. The isotope effect on N(2) fixation by soybeans (Glycine max [L] Merrill, variety Harosoy) and red clover (Trifolium pratense [L]) was determined from the difference in (15)N abundance between atmospheric N(2) and the total N of plants grown hydroponically with N-free nutrient solution. In soybeans the isotope effect was found to be +0.98 +/- 0.18 per thousand (beta = 0.99902). In clover the isotope effect was +1.88 +/- 0.14 per thousand (beta = 0.99812). The magnitude of these inverse isotope effects is small. However, they would lead to an underestimation of the amount of N(2) fixed, since the N of atmospheric origin which finally appears in the plant is made richer in (15)N by the inverse isotope effects than is atmospheric N(2), and, to that degree, is attributed to soil-derived N in the calculation.Isotopic fractionation associated with NO(3) (-) uptake by plants does not have a critical effect on estimates of N(2) fixation which are based on natural abundance of (15)N since the (15)N abundance of soil-derived N in plants is measured directly (i.e. after the N has undergone fractionation). Nevertheless, such fractionation is of some interest from the point of view of deciding upon the most appropriate sampling time. The isotope effect on NO(3) (-) uptake by a nonnodulating isoline of soybeans (variety Harosoy), marigold (Tagetes erecta [L]) and ryegrass (Lolium perenne [L]) was estimated from the difference between the (15)N abundance of the total N of plants grown hydroponically and that of NO(3) (-) supplied in the medium. It was found to be about -5 per thousand (beta = approximately 1.005).

Journal Article↗
PubMed1981

Stable Hydrogen Isotope Fractionations during Autotrophic and Mixotrophic Growth of Microalgae.

Isotope effects, studied with precision isotope ratio mass spectrometry, have been used to locate critical steps in the H metabolism of plants. By manipulating the growth conditions of versatile microalgae, the discrimination of H isotopes between water in the growth medium and the organically bonded H in carbohydrates from these microalgae was -100 to -120 per thousand and was regulated by both the light and the dark reactions of photosynthesis. Photosynthetic electron transport discriminated against the heavy isotope of H and formed a pool of reductant available for biosynthesis that was enriched in the light isotope. Growth in red or white light activated phosphoglyceric acid reduction and H isotope discrimination, when H was fixed into organic matter. An additional fractionation of -30 to -60 per thousand occurred during the biosynthesis of proteins and lipids and was associated with glycolysis. This fractionation paralleled the isotope effect seen in carbohydrate metabolism, indicating that H metabolism in photosynthesis was coupled with that in dark biosynthetic reactions via the pool of reductant, probably NADPH.

Journal Article↗
PubMed1985

Temperature Dependence of Carbon Isotope Fractionation in CAM Plants.

The carbon isotope fractionation associated with nocturnal malic acid synthesis in Kalanchoë daigremontiana and Bryophyllum tubiflorum was calculated from the isotopic composition of carbon-4 of malic acid, after appropriate corrections. In the lowest temperature treatment (17 degrees C nights, 23 degrees C days), the isotope fractionation for both plants is -4 per thousand (that is, malate is enriched in (13)C relative to the atmosphere). For K. daigremontiana, the isotope fractionation decreases with increasing temperature, becoming approximately 0 per thousand at 27 degrees C/33 degrees C. Detailed analysis of temperature effects on the isotope fractionation indicates that stomatal aperture decreases with increasing temperature and carboxylation capacity increases. For B. tubiflorum, the temperature dependence of the isotope fractionation is smaller and is principally attributed to the normal temperature dependences of the rates of diffusion and carboxylation steps. The small change in the isotopic composition of remaining malic acid in both species which is observed during deacidification indicates that malate release, rather than decarboxylation, is rate limiting in the deacidification process.

Journal Article↗
PubMed1989

Deuterium isotope effects on ethanol oxidation in perfused rat liver and in rats and rabbits in vivo: application to determine the contribution of various pathways.

The kinetic deuterium isotope effect, D(V/K), on ethanol oxidation was measured by the radiometric, competitive method using 14C-labelled ethanol containing deuterium in the (1-R) position. Acetate was isolated and used for the determination. Experiments were performed on rats either anaesthetized and laparotomized, or provided with indwelling catheters in a. carotis, v. cava and v. portae. Experiments were also made on perfused liver from rats pretreated with acetone, or a mixture of acetone and phenobarbital. Finally, intact non-anaesthetized rabbits were used. The apparent isotope effect in all in vivo experiments decreased rapidly in the presence of acetaldehyde as a consequence of the reversibility of the ADH reaction. In the case of rabbits and catheterized rats this problem was tackled by taking blood samples in quick succession, thus permitting extrapolation of the apparent isotope effect to the time of injection of the labelled ethanol. In anaesthetized rats injection of the ADH inhibitor isobutyramide was used to reduce the concentration of acetaldehyde and thereby the rate of decline of the apparent isotope effect. At high doses of isobutyramide the isotope effect was constant with time at about 1.9 suggesting the presence of non-ADH activity. In all three kinds of in vivo experiments the isotope effect ranged from 2.66 to 2.93. In the case of anaesthetized rats the mean value was 2.89 +/- 0.05 (S.D.). This figure is significantly different from that of rat liver ADH, P less than 0.001. As the figures for the initial isotope effects are minimum values the contribution of non-ADH ethanol oxidizing systems is likely to be small, probably less than 10 percent.

Acetaldehyde↗
PubMed2003

Determining lead sources in Mexico using the lead isotope ratio.

OBJECTIVE: Lead poisoning can, in some cases, be traced to a specific route or source of exposure on the basis of the individual's blood lead isotope ratio. To assess the major source of lead exposure among women residing in Mexico City, we compared blood, ceramic, and gasoline lead isotope ratios. MATERIAL AND METHODS: The study population, randomly selected from participants of a large trial, (1/1996-12/1996) comprised of 16 women whose lead levels exceeded 10 micrograms/dl and who reported using lead-glazed ceramics. Lead isotope ratios were performed on a Perkin Elmer 5000 Inductively Coupled Plasma Mass Spectrometer (ICP-MS) interfaced with a Perkin Elmer HGA-600MS Electrothermal Vaporization System (ETV). RESULTS: The isotope ratios (206Pb/204Pb, 207Pb/204Pb, and 208Pb/204Pb) of both the blood specimens and their corresponding ceramic specimens were highly correlated, with r = 0.9979, r2 = 0.9958, r = 0.9957, r2 = 0.9915 and r = 0.9945, r2 = 0.9890 values for the three isotope ratios, respectively, suggesting that the lead exposure most likely resulted from the use of these ceramic. Measurements of lead isotope ratios from leaded gasoline in use at the time of blood sampling, differed from those in blood and ceramics. CONCLUSIONS: Determining lead isotope ratios can be an efficient tool to identify a major source of lead exposure and to support the implementation of public health prevention and control measures. This paper is available too at: http://www.insp.mx/salud/index.html.

Ceramics↗
PubMed2005

Precise Zn isotopic ratio measurements of human red blood cell and hair samples by multiple collector-ICP-mass spectrometry.

Precise 66Zn/64Zn and 68Zn/64Zn isotopic ratios of biochemical samples have been measured using multiple collector-ICP-mass spectrometry (MC-ICPMS). In order to eliminate the mass spectrometric interferences on Zn isotopes (e.g., 64Ni+ and 136Ba2+), we chemically purified the analyte using an ion chromatographic technique. The resulting precisions of the 66Zn/64Zn and 68Zn/64Zn ratio measurements were 0.05/1000 and 0.10/1000 (2SD), respectively, which were enough to detect the isotopic variation of Zn in nature. Red blood cell (RBC) samples were collected from five volunteers (four males and one female), including a series of 12 RBC samples from one person through monthly-based sampling over a year. These were analyzed to test possible seasonal changes and variations in 66Zn/64Zn and 68Zn/64Zn ratios among the individuals. The 66Zn/64Zn and 68Zn/64Zn ratios for a series of 12 RBC samples collected over a year were 0.43/1000 and 0.83/1000 higher than the values of highly purified Zn metal (JMC Zn), and no seasonal change could be found. The 66Zn/64Zn and 68Zn/64Zn ratios for RBC samples collected from five volunteers did not vary significantly. In order to investigate Zn isotopic heterogeneity in a human body, Zn isotopic ratios of a hair sample collected from one of the volunteers was also analyzed. The 66Zn/64Zn and 68Zn/64Zn ratios for the hair sample were 0.59/1000 and 1.14/1000 lower than the mean value of RBC samples. This result demonstrates that detectable isotopic fractionation occurs in the human body. The data obtained here suggest that the isotopic ratios of trace metals could provide new information about transportation of metal elements in vivo.

Chromatography, Ion Exchange↗
PubMedDate not supplied

Deuterium isotope effect on the metabolism of N-nitrosodimethylamine and related compounds by cytochrome P4502E1.

1. Deuteration of N-nitrosodimethylamine (NDMA) decreases its carcinogenicity, and produces an isotope effect on its metabolism in vivo. Consistent with these results are the observations that deuteration caused a 5-fold increase in the apparent Km, but not the Vmax for the demethylation and denitrozation of NDMA in acetone-induced rat liver microsomes. These microsomes are a good source of cytochrome P4502E1. 2. For demethylation of Z-[2H3]NDMA and E-[2H3]NDMA, the Km values were indistinguishable, and were between the values for those of NDMA and [2H6]NDMA. Almost all the formaldehyde formed was derived from the non-deuterated methyl group, indicating a lack of stereoselectivity in the demethylation of NDMA. 3. NDMA and [2H6]NDMA displayed apparent Ki values of 59 and 441 microM, respectively, for N-nitrosodiethylamine deethylase, showing an apparent isotope effect of 0.13, and displayed an isotope effect of 0.21 in the Ki values for p-nitrophenol hydroxylase. 4. With acetone and deuterated acetone as inhibitors for p-nitrophenol hydroxylase, the isotope effect on the Ki was 0.11. Similar deuterium isotope effects were also observed with acetone and dimethylformamide as competitive inhibitors for NDMA demethylase. 5. In the microsomal oxidation of ethanol, a deuterium isotope effect of about five was observed in the Vmax/Km when carbon-1 was deuterated, but was not observed in the Vmax. 6. Results illustrate a unique deuterium isotope effect on the Km values of reactions catalysed by P4502E1.

Animals↗
PubMed2000

Isotope selection for permanent prostate implants? An evaluation of 103Pd versus 125I based on radiobiological effectiveness and dosimetry.

Transperineal interstitial permanent prostate brachytherapy (TIPPB) has become an increasingly popular treatment for early-stage/favorable-risk adenocarcinoma of prostate. Within TIPPB, permanent implants often use either (103)Pd (T(1/2) = 17 days) or (125)I (T(1/2) = 60 days). This review compares the radiobiological and treatment planning effectiveness of (103)Pd and (125)I implants by using the linear-quadratic model with recently published data regarding: prostate tumor cell doubling times, T(pot), alpha and alpha/beta, ratio. The tumor potential doubling times (T(pot)) were determined based on recently published proliferation constants (K(p)). The initial slope of the cell radiation dose survival curve, alpha, the terminal slope beta and the alpha/beta ratio were taken from recent published clinical and cellular results. The total dose delivered from each isotope was the dose used clinically, that is, 120 Gy for (103)Pd and 145 Gy for (125)I. Dale's modified linear-quadratic equation was used to estimate the biological effective dose, the cell-surviving fraction, the effective treatment time, and the wasted radiation dose for different values of T(pot). Treatment plans for peripherally loaded implants were compared. The T(pot) reported for organ-confined prostate carcinomas varied from 16 to 67 days. At short T(pot) both isotopes were less effective, but (103)Pd had much less dependence on T(pot) than (125)I. However, at long T(pot) both isotopes produced similar effects. The minimum surviving fraction for exposure to (103)Pd decreased from 1.40 x 10(-4) to 1.31 x 10(-5) as the T(pot) increased from 16 to 67 days. By contrast for exposure to (125)I, the minimum surviving fraction decreased from 3.98 x 10(-3) to 1.98 x 10(-5) over the same range of T(pot). A comparison of treatment plans revealed that (103)Pd plans required more needles and seeds; however, this was a function of seed strength. Both isotopes had similar dose-volume histograms for prostate, urethra, and rectum. The theoretical prediction of effectiveness using the linear quadratic equation for the common clinically prescribed total radiation doses indicated that (103)Pd should be more effective than (125)I because it had less dependence on T(pot). The greatest benefit of (103)Pd was shown to be with tumors with a short T(pot). Although the regrowth delay would be longer with (125)I, the benefit was inconsequential compared with the very slow doubling times of localized prostate cancer. Treatment planning with either isotope revealed no significant differences. These findings may explain why clinically there seemed to be no clear difference in treatment outcome with either isotope. Based on these predictions, we recommend a clinical trial to compare the efficacy of the two isotopes.

Adenocarcinoma↗
PubMed1975

Validation of use of 11,12-2H-labeled chenodeoxycholic acid in isotope dilution measurements of bile acid kinetics in man.

Chenodeoxycholic acid labeled with 2H in the 11 and positions was prepared by catalytic reduction of delta 11-12 unsaturated derivatives of cholic acid. To validate the use of this stable isotope for the determination of bile acid kinetics by isotope dilution, it was administered to seven normal male volunteers simultaneously with [24-14C]chenodeoxycholic acid. Bile was collected at regular intervals over the following 5 days, and the chenodeoxycholic acid pool size and fractional turnover rate were determined from the specific activity decay curve for 14C and from the isotopic abundance curve for 2H. Estimates of the pool size by both isotopes showed a correlation of r = 0.95 and similar precision. Synthesis rate, the product of pool size and fractional turnover rate, also showed good agreement (r = 0.97), Because previous investigations have shown that bile acids tagged with hydrogen isotopes at the 11 and 12 positions are stable in man, the present data suggest that 11, 12-2H-labeled bile acids may be used in place of radioactive isotopes for valid isotopic measurement of bile acid kinetics in healthy infants and children.

Adult↗
PubMed1986

Mechanism and activation for allosteric adenosine 5'-monophosphate nucleosidase. Kinetic alpha-deuterium isotope effects for the enzyme-catalyzed hydrolysis of adenosine 5'-monophosphate and nicotinamide mononucleotide.

The kinetic alpha-deuterium isotope effect on Vmax/Km for hydrolysis of NMN catalyzed by AMP nucleosidase at saturating concentrations of the allosteric activator MgATP2- is kH/kD = 1.155 +/- 0.012. This value is close to that reported previously for the nonenzymatic hydrolysis of nucleosides of related structure, suggesting that the full intrinsic isotope effect for enzymatic NMN hydrolysis is expressed under these conditions; that is, bond-changing reactions are largely or completely rate-determining and the transition state has marked oxocarbonium ion character. The kinetic alpha-deuterium isotope effect for this reaction is unchanged when deuterium oxide replaces water as solvent, corroborating this conclusion. Furthermore, this isotope effect is independent of pH over the range 6.95-9.25, for which values of Vmax/Km change by a factor of 90, suggesting that the isotope-sensitive and pH-sensitive steps for AMP-nucleosidase-catalyzed NMN hydrolysis are the same. Values of kH/kD for AMP nucleosidase-catalyzed hydrolysis of NMN decrease with decreasing saturation of enzyme with MgATP2- and reach unity when the enzyme is less than half-saturated with this activator. This requires that the rate-determining step changes from cleavage of the covalent C-N bond to one which is isotope-independent. In contrast to the case for NMN hydrolysis, AMP nucleosidase-catalyzed hydrolysis of AMP at saturating concentrations of MgATP2- shows a kinetic alpha-deuterium isotope effect of unity. Thus, covalent bond-changing reactions are largely or completely rate-determining for hydrolysis of a poor substrate, NMN, but make little or no contribution to rate-determining step for hydrolysis of a good substrate, AMP, by maximally activated enzyme. This behavior has several precedents.

Adenosine Monophosphate↗