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PubMed1975

Matrix simulation of duodenal crypt cell kinetics. II. Cell kinetics following hydroxyurea.

The perturbed cellular kinetics of the duodenal crypt following a single injection of hydroxyurea (HU) have been simulated using matrix algebra. Following the direct effects of HU (S-phase cytotoxicity and a G1/S block) the crypt cell kinetics undergo several alterations. Previously documented alterations include: (1) a temporary partial synchronization of the surviving cells, (2) a shortening of the cell-cycle transit time, and (3) recruitment of normally non-proliferating cells into active proliferation. These conclusions have been extended by constructing several different complex but theoretically possible recovery models and the validity of each of these models has been evaluated by simulating the following biological data: the number of cells in the S and M-phase of the cell cycle, total viable cells per crypt, and the per cent labeled mitosis and the number of labeled cells following 3H-TdR injections at 9 and 21 hr after HU treatment. The model which showed visually the best overall agreement with all sets of the data was chosen as "most probable' and leads to the following interpretations. Immediately after the end of the HU block (i.e. 5 hr after HU injection) the modal cell-cycle transit time is reduced to 8 hr. By 17 hr after HU, the modal transit time is increased to 10 hr. Repopulation of the proliferating compartment, i.e. restoration of the proliferating compartment back to the control value, occurs between 12 and 17 hr after HU injection and probably consists of both recycling of the proliferating cells (i.e. they do not progress up into the non-proliferating compartment) and recruitment of the non-proliferating cells into active proliferation. Also, the rate at which the non-proliferating cells move onto the villi is reduced temporarily. The overall recovery process results in a crypt which temporarily is larger than control and produces villi cells at a rate which is faster than the control. The time when the crypt size and villus cell production rate return to normal cannot be established using the available data.

Animals↗

PubMed1975

Investigations on the kinetic mechanism of octopine dehydrogenase. 1. Steady-state kinetics.

The kinetic mechanism of action of octopine dehydrogenase was investigated. This enzyme catalyses the reversible dehydrogenation of D-octopine to L-arginine and pyruvate, in the presence of nicotinamide-adenine dinucleotide. Initial velocity and product inhibition studies were carried out in both directions. Most of the results are consistent with a bi-ter sequential mechanism where NAD+ binds first to the enzyme followed by D-octopine, and the products are released in the order L-arginine, pyruvate and NADH. Various kinetic parameters were determined for each reactant at 33 degrees C, at pH 9.6 for NAD reduction, at pH 6.6 for NADH oxidation.

Animals↗

PubMed1981

31P NMR study of the kinetics of binding of myo-inositol hexakisphosphate to human hemoglobin. Observation of fast-exchange kinetics in high-affinity systems.

The association and dissociation kinetics of the complexes of myo-inositol hexakisphosphate (P6-inositol) with deoxyhemoglobin (Hb) and carboxyhemoglobin (HbCO) have been investigated by 31P NMR between pH 6.8 and pH 5.5. These complexes represent high-affinity systems with binding constants varying between 10(5) M-1 and 2 X 10(9) M-1. 31P NMR spectra of P6-inositol were recorded in the presence of hemoglobin as a function of the P6-inositol/hemoglobin molar ratio. It appeared that the exchange of the polyphosphate molecule between the solution and the central cavity binding site is fast on the NMR time scale. This observation cannot be reconciled with a single-step binding mechanism of P6-inositol to hemoglobin. Analysis of the spectra revealed the occurrence of additional binding of P6-inositol to both Hb and HbCO. This binding was also observed in pH-state experiments performed at low ionic strength. 31P NMR experiments carried out with hemoglobin of which the alpha-chain N termini were carbamylated, strongly suggest that these termini constitute the additional binding site for P6-inositol. A model is proposed which accounts for the enhancement of exchange kinetics in these high-affinity systems. In this model a rapid migration is assumed for P6-inositol between the central cavity binding site and an entry/leaving site on the hemoglobin molecule. Based on this model 31P NMR linewidths and chemical shift patterns for this three-site exchange problem were calculated.

Carboxyhemoglobin↗

PubMed1988

Cancer and aging: from the kinetics of biological parameters to the kinetics of cancer incidence and mortality.

Epidemiologic and biological data strongly support the existence of a strict link between cancer and aging. In spite of the relevance of the problem, there were numerous pitfalls in epidemiologic investigation until a few years ago. An apparent decrease of cancer incidence in old age was revealed to be a misconception based on lack of sufficient appreciation for changing population size. But not all problems are solved by using age-specific cancer incidence, as recently stressed by some authors. At very advanced ages a slowing of the rate of increase of age-specific cancer incidence is clearly demonstrated. These findings apparently clash with the majority of biological data and suggest that some mechanism may develop at advanced ages capable of decreasing cancer susceptibility. In this paper, it will be shown that just a slowing-down kinetics is predicted for cancer incidence by using a mathematical model of mortality kinetics recently proposed in the gerontologic field. The slowing of the increasing rate or even a decreasing trend of cancer incidence of an aging population is compatible with a continuously accelerating pace of loss of physiological capacity of the single subjects, as with advancing age there is a selection of individuals with better physiological functions.

Adult↗

PubMed2003

Na,K-pump reaction kinetics at the tip of a patch electrode: derivation of reaction kinetics for electrogenic and electrically silent reactions during ion transport by the Na,K-ATPase.

Patch-clamp electrophysiological techniques allow manipulations of electrochemical driving forces for ion transport by the Na,K-ATPase. For this reason, this technique has been used to study steady-state ion transport properties of the Na,K-ATPase. High temporal resolution during these manipulations also permits rapid reactions, such as extracellular ion-binding reactions, to be measured as charge movements when the enzyme is engaged in electroneutral ion exchange modes. Just as useful, but less widely recognized, is the ease with which electrophysiological techniques can be used to critically study reaction steps that do not directly involve ion binding. Three studies are briefly presented to show how pre-steady-state and/or steady-state electrophysiological techniques can be used to study ion-binding reactions in a novel fashion and the kinetics of electrically silent reaction steps of this enzyme. The reaction kinetics derived from each of these studies can be used to attain detailed mechanistic information about ion transport by the Na,K-ATPase.

Amines↗

PubMed2001

Relationship of exo-beta-D-galactofuranosidase kinetic parameters to the number of phosphodiesters in Penicillium fellutanum peptidophosphogalactomannan: enzyme purification and kinetics of glycopeptide and galactofuran chain hydrolysis.

Extracellular Penicillium fellutanum exo-beta-D-galactofuranosidase, with a mass of 70 kDa, was purified to apparent homogeneity. The enzyme was used to investigate the influence of phosphodiesters of the peptidophosphogalactomannans pP(2)GM(ii) and pP(25)GM(ii) (containing 2 and 25 phosphodiester residues, respectively, per mol of polymer) on the kinetic parameters of galactofuranosyl hydrolysis of these two polymers, of 1-O-methyl-beta-D-galactofuranoside, and of two galactofuranooligosaccharides. The enzyme did not hydrolyze phosphorylated galactose residues of pP(2)GM(ii) or pP(25)GM(ii). The k(cat)/K(m) value for pP(25)GM(ii) is 1.7 x 10(3) M(-1) s(-1), that for 1-O-methyl-beta-D-galactofuranoside is 1.1 x 10(4) M(-1) s(-1), that for pP(2)GM(ii) is 1.7 x 10 (4) M(-1) s(-1), and those for 5-O-beta-D-galactofuranooligosaccharides with degrees of polymerization of 3.4 and 5.5 are 1.7 x 10(5) and 4.1 x 10(5) M(-1) s(-1), respectively. Variability in the k(cat)/K(m) values is due primarily to differences in K(m) values; the k(-1)/k(1) ratio likely provides the most influence on K(m). k(cat) increases as the degree of polymerization of galactofuranosyl residues increases. Most of the galactofuranosyl and phosphocholine residues were removed by day 8 in vivo from pP(x)GM(ii) added to day 3 cultures initiated in medium containing 2 mM phosphate but not from those initially containing 20 mM phosphate. The filtrates from day 9 cultures initiated in 2 mM inorganic phosphate in modified Raulin-Thom medium contained 0.2 mM inorganic phosphate and 2.2 U of galactofuranosidase ml(-1)h(-1). No galactofuranosidase activity but 15 mM inorganic phosphate was found in filtrates from day 9 cultures initiated in 20 mM phosphate. In vivo the rate of galactofuranosyl hydrolysis of pP(x)GM(ii) and of related polymers is proportional to the k(cat)/K(m) value of each polymer. The kinetic data show that the k(cat)/K(m) value increases as the number of phosphodiesters of pP(x)GM(ii) decreases, also resulting in an increase in the activity of exo-beta-D-galactofuranosidase.

Carbohydrate Sequence↗

PubMed1986

Kinetics of methaemoglobin production. (2). Kinetics of the cyanide antidote p-aminopropiophenone during oral administration.

The kinetics of methaemoglobin production by orally administered p-aminopropiophenone (PAPP) was studied by using a kinetic model previously developed to describe methaemoglobinaemia consequent on intravenous injection of PAPP. Both ISIS, a simulation package, and NONLIN, a non-linear least-squares regression analysis program, were used to analyse the data. Some modification of the model was necessary to describe oral profiles and 40-50% of the administered PAPP appeared to be being metabolized at first pass to a non-active metabolite.

Administration, Oral↗

PubMed1984

A U-shaped bioartificial pancreas with rapid glucose-insulin kinetics. In vitro evaluation and kinetic modelling.

The lag in insulin release in response to glucose is an obstacle to the development of hybrid pancreatic devices, in which an artificial membrane protects transplanted islets against immune rejection. We designed a U-shaped bioartificial pancreas, in which the blood channel surrounds the islet chamber consisting of two flat membranes; blood circulates successively above the first membrane and then in the reverse direction, below the second membrane. Isolated rat islets were introduced into the chamber, which was perfused with Krebs buffer, and the kinetics of insulin release in response to glucose was determined. During a 20-min, 2.8-20-mM, square-wave glucose stimulation, insulin release in the effluent of the device rose from 0.7 +/- 0.2 to 3.2 +/- 1.0 ng/100 islets/min (P less than 0.05) within 3 min, and reached a maximal level of 12.8 +/- 3.3 ng/100 islets/min at 10 min; 5 min after the return of the glucose concentration to substimulatory level, insulin release dropped from 11.3 +/- 1.5 to 8.0 +/- 1.7 ng/100 islets/min (P less than 0.05), and reached basal value (1.0 +/- 0.2 ng/100 islets/min) 40 min after the end of the stimulation. A 0.1-mM/L/min ramp increase in glucose concentration triggered a significant rise in insulin release (P less than 0.02) when the glucose concentration reached 5.3 +/- 0.2 mM; islets concomitantly perifused within a chamber set up without membrane responded to the same glucose stimulation 5 min earlier. For up to 1000 islets, insulin release in response to glucose was linearly correlated to the number of islets (N = 12, P less than 0.01), indicating that insulin did not significantly inhibit its own secretion in this system. Finally, during glucose stimulation, the insulin concentration in the effluent from the chamber was found to be four times the concentration present at the turning point of the blood channel, suggesting that insulin was transferred into the perfusing medium in part by a countercurrent flux of ultrafiltrate crossing the membranes. We present herein the kinetic modelling of glucose and insulin transfer in this "ultrafiltration chamber," whose functional characteristics are compatible with closed-loop insulin delivery.

Animals↗

PubMed1976

[Steady-state kinetics of electron transfer through the cytochrome chain of uncoupled submitochondrial particles. General kinetic analysis].

Steady-state kinetics of electron transfer through the cytochrome chain of uncoupled ultrasonic submitochondrial particles at different pH values were studied. The rate constants calculated according to Pring's equation (k1=V/Prpoxt i+1) were found to increase linearly with the increase in the rate of electron transfer. Linearity was observed, however, only at relatively low rates of electron transfer. Several kinetic models were developed and analysed to fit the experimental data on the basis of the suggested activation of respiratory chains induced by their functioning. The best agreement with the experimental data was obtained with the model implying that the rate of activation of the electron carriers is directly proportional to the overall rate of electron transfer and the portion of non-activated respiratory chains in the system. It followed therefrom that electron transfer through already activated chains induced activation of adjacent non-activated chains. This model made it possiple to determine the rate constants for non-activated (ki) and activated (k) carrier states and the life-times of activated carriers (tau).

Animals↗

PubMed1976

Kinetics and mechanism of degradation of some 5-allylbarbituric acid derivatives. Part 3: Kinetics of solvolysis of major intermediates of 5.5-diallylbarbituric acid degradation.

Solvolysis of N-diallylacetylurea and 5.5-diallylmalonuric acid was investigated in the pH range ca. 8--12 by means of spectrophotometric and t.l.c. methods. Their log k--pH profiles were constructed from the experimental results obtained by degradation at 70 degrees C. Therefore, specific catalytic rate constants and pKa's were derived. The kinetic mechanism of N-diallylacetylurea solvolysis, resulting among other things from the so-called kinetic salt effect, depends on hydroxyl-ion attack on its undissociated and monoanionic forms. However, the degradation of alpha.alpha-diallylmalonuric acid in the pH range 10--12 is an example of specific base catalysis which can be explained by hydroxyl-ion attack on its monoanionic species. The degradation of alpha.alpha-diallylmalonuric acid below pH=10 does not follow a theoretical equation postulated, because the spectrophotometric method does not allow monitoring the formation of N-diallylacetylurea in the presence of the above acid. Thin-layer chromatography was used to check different pathways of transformations of the intermediate studies.

Allyl Compounds↗

PubMed2004

[High performance liquid chromatography in cortisol kinetics and its kinetic parameters in patients treated with exogenous glucocorticoids].

The kinetics of cortisol was investigated in 26 healthy subjects and in 9 patients with rheumatoid arthritis induced by exogenous glucocorticosteroids. The cortisol concentration was determined in blood serum by using a high-efficiency liquid chromatography method. The cortisol kinetic parameters were found by empirically constructed formulae. An inadequate synthesis of cortisol was found in patients with rheumatoid arthritis after prednisolone administration. The results can be used for evaluating the pharmacodynamic properties of glucocorticosteroids.

Adult↗

PubMedDate not supplied

[A kinetic model of the cytochrome bf complex. Evaluation of kinetic parameters].

A kinetic model of the cytochrome bf complex was developed on the assumption that the Q-cycle operates. The bf complex was considered as a membrane enzyme catalyzing the electron transfer from plastoquinol to plastocyanine, which is coupled with proton translocation from the chloroplast stroma to the thylakoid lumen. The dependence of the electron transfer rates on the value of the transmembrane electric potential was taken into account. The model was applied to describe the experimental data on the flash-induced turnover of cytochromes b, plastocyanine, and the kinetics of proton deposition in the thylakoid lumen. The estimation of model parameters was performed.

Cytochrome b6f Complex↗

PubMed1990

Unusual transient- and steady-state kinetic behavior is predicted by the kinetic scheme operational for recombinant human dihydrofolate reductase.

Association and dissociation rate constants obtained by stopped-flow spectroscopy have permitted definition of a kinetic scheme for recombinant human dihydrofolate reductase that correctly predicts full time course kinetics of the enzymatic reaction over a wide range of substrate and product concentrations. The scheme is complex compared with that for the bacterial enzyme and involves branched pathways. It successfully accounts for observed rapid hysteresis preceding steady state and for the nonhyperbolic dependence of steady-state rate on substrate and product concentrations. The major branch point in the catalytic cycle occurs at E.NADP.H4folate because either NADP or H4folate can dissociate from the ternary product complex (koff = 84 s-1 and 46 s-1, respectively). The rate of conversion of enzyme-bound substrates to products is very fast (k = 1360 s-1) and nearly unidirectional (Kequ = 37) so that other steps limit the catalytic rate. At saturating substrate concentrations these steps include release of NADP and H4folate from E.NADP.H4folate and release of products from the two abortive complexes E.NADPH.H4folate (koff = 225 s-1) and E.NADP.H4folate (koff = 4.6 s-1). Since NADP dissociates slowly from E.NADP.H2folate nearly 90% of the enzyme accumulates as this complex at steady state. Nonetheless, the catalytic rate is maintained at 12 s-1 by rapid flux of a small portion of the enzyme through an alternate branch. At physiological concentrations of substrates and products the steady-state rate is limited primarily by the rate of H2folate binding to E.NADPH so that the enzyme is extremely efficient.

Humans↗

PubMed1975

Kinetic studies of carboxypeptidase Y. I. Kinetic parameters for the hydrolysis of synthetic substrates.

Kinetic parameters for carboxypeptidase Y [EC 3.4.12.1], characterized as a nonspecific enzyme, are given for the hydrolysis of a series of acylated peptides, acylated amino acid esters, and amides. We confirmed that the enzyme released COOH-terminal proline and beta-alanine at an appreciable rate, as well as neutral amino acids with aromatic and aliphatic side chains at a very high speed. The rates of hydrolysis of ester and amide substrates were compatible with those produced by chymotrypsin [EC 3.4.21.1]. Stereospecificity was also demonstrated by the failure to hydrolyze peptide, ester, amide, and anilide substrates containing a D-amino acid. The effects of pH, solvents, and salt concentrations on the kinetic parameters of hydrolysis of peptide and ester substrates are also described.

Anilides↗

PubMed1989

Interaction of bisantrene anti-cancer agents with DNA: footprinting, structural requirements for DNA unwinding, kinetics and mechanism of binding and correlation of structural and kinetic parameters with anti-cancer activity.

A topoisomerase I assay in conjunction with covalently closed circular DNA afforded unwinding angles for a series of eight analogs of the anti-cancer agent bisantrene. Values ranging from 33 degrees to zero comprised three classes wherein the extent of DNA interaction correlates with anti-cancer activity. The binding of bisantrene compounds to T4 DNA suggests at least partial interaction via the minor groove. MPE footprinting evaluation of bisantrene showed no evidence for selective protection of a Hind III-EcoRI fragment of pBR322 suggesting a sequence neutral binding mode. Stopped flow spectrophotometry studies indicate an association rate constant for bisantrene with DNA of greater than 1 x 10(7) M-1 S-1 at 20 degrees at ionic strength of 0.1 and is considerably slower than ethidium or propidium at all ionic strengths. At least two exponential components are required to match the kinetic curves indicating a biphasic mechanism and estimates of k1 and k2 were obtained for seven drugs. The ionic strength dependence of the surfactant driven dissociation of bisantrene is in accord with a competitive mechanism for intercalation of the drugs at alternative sites. The residence time and t1/2 (app) for bisantrene are slightly larger for poly d(G.C)2 than poly d(A.T)2 and calf thymus DNA is at an intermediate value. Considerations of structural factors in the drug dissociation kinetics permit a correlation with observed anti-cancer properties of these bisantrene analogs.

Animals↗

PubMed1986

[Kinetics of germ killing and damage to selected bacterial enzymes by thermal and chemical influences. I. Theoretical background of killing and enzyme inhibition kinetics].

Thermal and chemical influences on microorganisms and the kinetics of microbicidal processes are described in terms suitable to define the resistance of microbes to heat and disinfectants resp. sterilisants. Interactions between active substances (e.g. disinfectants) and enzymes are formulated in equations, and the parameters of kinetics of inactivating enzymes (e.g. Ki-values) are derived. They permit a gradual evaluation of efficacy of microbicidal agents irrespective of their concentration.

Bacteria↗

PubMed1985

[Kinetics of the antimicrobial effect in a dynamic system: the microcalorimetric recording method and choice of parameters for characterizing kinetic curves].

The kinetics of the in-vitro antimicrobial effect of sisomicin on E. coli, A 20363 was studied microcalorimetrically in a dynamic model simulating the pharmacokinetic profiles (intramuscular administration in a dose of 1 mg/kg) of the antibiotic obeying the one-compartmental model with first-order absorption. The microcalorimetric method was more accurate than the count of the colony forming units (CFU). Unlike the CFU method, it permits continuous recording of the process and unlike the turbidimetric method, it is more sensitive and selective. For quantitative characteristic of the curves of the antimicrobial effect kinetics it is suggested to use a new parameter, the effect duration (Td) which is determined by the difference in the moment of the antibiotic administration into the dynamic model (Tin) and the moment (Tout) when the rate of heat production or the number of the CFU or the optical density during the microbial secondary growth was the same as that at Tin. It was shown that the values of Td estimated in experiments with recording of the antimicrobial effect by different methods are similar. Evaluation of Td may be useful in predicting the optimal dosing intervals.

Calorimetry↗

PubMed1982

[Study on the kinetics of mucus secreting cells in the gastrointestinal tract --effects of various drugs and hormones on the cell kinetics of the generative zone in mouse gastric mucosa].

The effects of various antiulcer drugs and hormones on the cell kinetics of the mouse gastric mucosa were studied using an autoradiographic technique with 3H-thymidine. The drugs or hormones were administered orally or parenterally once or twice a day for 7 consecutive days, and 3H-thymidine was injected after the last administration of the drug. The autoradiograph was prepared and then the labeling index was counted. Cimetidine (100 mg/kg X 2/day, p.o.), geranylgeranylacetone (GGA, 100 mg/kg X 2/day, p.o.) and Cu-chlorophyllin-Na (300 mg/kg X 2/day, p.o.) did not show any effect on the labeling indices in both the tissues of the fundic and pyloric glands, while carbenoxolone (100 mg/kg X 2/day), p.o.) reduced the labeling index in the pyloric glands. Tetragastrin (1 mg/kg X 1/day, i.m.) increased the labeling index in the fundic glands, whereas secretin did not affect it. Hydrocortisone (100 mg/kg X 1/day, S.C.) reduced the labeling index in the fundic glands, and this reducing effect was prevented by combining hydrocortisone with GGA. From these results, it was indicated that the labeling index in the normal mouse gastric generative zone was no influenced by the tested antiulcer drugs, except carbenoxolone; but the index was influenced by tetragastrin and hydrocortisone, especially in the fundic glands. It was also suggested that the changes in the cell kinetics of the gastric mucosa could be related to the etiology of gastric ulcer since there was a possibility that geranylgeranylacetone could control the action of hydrocortisone, an ulcerogenic agent, on the gastric mucosal cell-cycle.

Animals↗