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PubMed1985

Cyanate and temperature regulation in anephric rabbits.

Knochel and Seldin proposed that the lowered body temperature observed during uremia was caused by an elevation in the circulating levels of cyanate. To test this hypothesis, normal rabbits were infused with varying concentrations of sodium cyanate. Infusion of pharmacological doses of cyanate (plasma concentration rose to 1,080 +/- 70 microM, n = 5) resulted in reductions in body temperature similar to that found during uremia; however, when normal rabbits were nephrectomized the plasma cyanate concentration only rose from 3.7 +/- 1.6 to 18 +/- 1.8 microM (n = 8) by 1-day postnephrectomy (body temperature fell 0.33 +/- 0.1 degrees C, n = 6). Plasma cyanate concentration did not rise further on days 2 and 3 postnephrectomy, despite a continued fall in body temperature. Infusion of cyanate in control rabbits to plasma concentrations attained 1-3 days postnephrectomy did not result in a fall in body temperature. Based on the failure of pathophysiological concentrations of cyanate to cause a reduction in the body temperature of normal rabbits, we conclude that cyanate is not responsible for the lowered body temperature associated with the acute response to uremia.

Animals↗
PubMed1981

Effects of cyanate on the distribution of isotope-labeled H2O and extracellular markers in rat liver and tumors.

Previous work has shown that administration of sodium cyanate inhibits the uptake of several metabolites in tumors under conditions in which there is generally no inhibition in normal tissues of the rat. In the present work, it was found that cyanate treatment inhibits the distribution of 3H2O, [3H]methoxyinulin, and [14C]sucrose in rats with greater effects in the tumors than the normal tissues examined. Tumor-bearing rats received i.p. injections of sodium cyanate (250 mg/kg body weight). After 60 min, the rats received s.c. injections of 3H2O. Treatment with cyanate decreased the radioactivity in blood and liver, but greater effects were seen in five transplanted tumors (LK1 colon tumor and Morris hepatomas 5123C, 7288CTC, 7777, and 9618A2). At 10 min after injection of 3H2O, the mean radioactivities in tumors of cyanate-treated rats were 11 to 23% of control values and in some tumors were still less than in controls at 60 min after isotope injection. Evidence was obtained that the action of cyanate was not due to osmotic effects or loss of water from the tissues. The distribution of the extracellular markers [3H]methoxyinulin and [14C]sucrose was also decreased in hepatomas in cyanate-treated rats. The data do not exclude effects on membrane permeability but suggested that cyanate decreased circulation in the tumors.

Animals↗
PubMed1988

pH-related effects of sodium cyanate on macromolecular synthesis and tumor cell division.

In past work, the selective effects of sodium cyanate on macromolecular synthesis in tumors have not been seen with cells in culture. We have explored the possibility that differences in the response of tumor cells to cyanate in vivo and in vitro may be related to the pH in the environment to which cells are exposed. When rat hepatoma (HTC) cells were incubated with sodium cyanate (0.25 mg/ml), there was a greater inhibition of precursor incorporation into RNA and DNA with a decrease in pH from 7.4 to 6.6. At pH 7.4 there was no significant effect of sodium cyanate on the incorporation of [3H]leucine into protein of rat hepatocytes and HTC cells, but at pH 6.6 there were decreases of 50% or greater. The time of response and the reversibility of the inhibitory effects of sodium cyanate were not those anticipated from carbamoylation of amino groups but were compatible with modification of sulfhydryl groups. The uptake of [14C]sodium cyanate in HTC cells and human colon cancer (HT29) cells was greater at pH 6.6 than at 7.4. Over a period of 4 days there was a slower rate of cell division by HTC and HT29 at pH 6.6 than at pH 7.4. The addition of sodium cyanate caused a further reduction in the rate of proliferation, and at a concentration of 0.25 mg sodium cyanate/ml there were decreases in cell numbers. The data suggested that a lower interstitial pH in tumors than normal tissues would result in greater sensitivity to inhibitory effects of sodium cyanate on macromolecular synthesis.

Animals↗
PubMed1990

Ibuprofen, a putative anti-cataract drug, protects the lens against cyanate and galactose.

Cataract, the major cause of blindness world-wide, may be caused partly by modification of lens proteins by carbamylation and non-enzymic glycosylation (glycation) in some patients. Aspirin has been found to protect against these modifications and to prevent cyanate-induced opacification occurring in whole rate lenses. Ibuprofen is an aspirin-like anti-inflammatory drug which appeared as a protective factor against cataract in an Oxford case-control study. The binding of cyanate, galactose and glucose 6-phosphate to lens proteins, and the effect of ibuprofen on this reaction was investigated, as was cyanate-induced opacification in whole rat lenses. Labelled metabolite was incubated with bovine lens homogenate in the presence and absence of ibuprofen, and the incorporation of label into the lens homogenate was followed. Simultaneous and preincubation experiments were performed. Intact rat lenses were incubated in culture medium with and without cyanate and ibuprofen. The phase separation temperature was noted as the temperature at which opacity first appeared on cooling. Cyanate, galactose and glucose 6-phosphate bind progressively to lens proteins. Simultaneous incubation with ibuprofen reduces cyanate and galactose binding but not glucose 6-phosphate. Ibuprofen protects against opacities due to cyanate-induced phase separation. Ibuprofen has protected against cataract in the models of cataractogenesis in this study. It appears to have a different mechanism of action from that of aspirin. These studies provide some support for the idea, based on epidemiological findings, that ibuprofen might be a useful anti-cataract drug.

Animals↗
PubMed2000

Cyanate as a hemolytic factor.

During advanced renal failure, and particularly in patients with end-stage renal disease, proteins are carbamylated as a result of a reaction with cyanate. If the carbamylation of proteins adversely alters their biologic activities and structures, then urea must be viewed as an uremic toxin, rather than a surrogate. Therefore, we studied in this paper the role of cyanate as a hemolytic factor of erythrocytes to explain anemia observed in patients with high blood urea levels due to inadequate dialysis. Cyanate was added to make the final concentration 150, 300 and 600 nmol to each test tube containing the final concentration of 140 x 10(6) with human erythrocytes per mL of phosphate buffered saline solution. And they were incubated at 37 degrees C for 24, 48 and 72 hours. The extent of hemolysis and carbamylation was monitored. The levels of hemolysis and carbamylated erythrocytes increased as the time of exposure to cyanate increased from 24 hours to 72 hours. Furthermore, those increased as cyanate concentration in the incubation media rose from 150 nmol to 600 nmol. Cyanate can induce hemolysis by carbamylation of erythrocytes. Urea, through cyanate, may contribute to hemolysis. If one extrapolates these results to patients with end-stage renal disease, it may help explain one of the reasons for the anemia in patients with high levels of BUN due to inadequate dialysis.

Anemia, Hemolytic↗
PubMed1997

[14C]cyanate labeling of sheep red cells: covalent binding to hemoglobin continues in vivo for a day.

The sheep is a useful model to study fetal and newborn physiology including perinatal erythropoiesis and red cell kinetics. A practical, economical method for measuring red cell survival (RCS) in sheep would be very valuable. However, 51Cr is unsatisfactory, and suitable alternatives have not been published. In the course of investigating [14C]cyanate as a label for sheep red cells, we observed continued covalent labeling over 24 h in vivo that was great enough to introduce a substantial artifact into two commonly used parameters of RCS: posttransfusion recovery (PTR24) and time to 50% decrease (T50) when referenced to time zero. In a simulation of in vivo conditions, the amount of 14C bound to Hb increased 26 +/- 6% (mean +/- 1 SD, n = 11) over 24 h. To investigate the mechanism of the increasing 14C bound, acid-acetone extraction, molecular sieve chromatography, and density gradient separation were used separately or in combination to quantitate intracellular free 14C and 14C covalently bound to intracellular proteins. Free 14C decreased as protein-bound [14C]cyanate increased. These studies provide evidence that covalent binding of [14C]cyanate to intracellular Hb continues in vivo for the first 24 h and that the source of the increase is intracellular free [14C]cyanate. We conclude that 1) PTR24 cannot be accurately determined by [14C]cyanate unless labeled red cells are incubated before infusion to allow the cyanate reaction to approach completion and 2) RCS by [14C]cyanate should be referenced to blood concentrations at 24 h.

Acetone↗
PubMed1981

Activation of sodium cyanate for selective inhibition of protein synthesis in cultured tumor cells.

Sodium cyanate, a selective inhibitor of protein synthesis in animal tumors in situ, has no comparable effect when added to tumor cells in culture. However, a rapid inhibition of protein synthesis in cultured tumor cells can be achieved by reaction of cyanate with the drug-metabolizing system of liver microsomes. Procedures are described for the induction, preparation, and testing of an active cytochrome P-450 fraction which converts cyanate to a short-lived dialyzable metabolite that selectively inhibits amino acid incorporation in tumor cells without a corresponding effect on protein synthesis in normal cells. The suppression of tumor protein synthesis is not due to a general toxicity reaction because thymidine incorporation into the DNA of tumor cells is not inhibited by the cyanate metabolite. When HeLa cells are exposed to sodium butyrate, a substance reported to suppress the malignant phenotype in several tumor cell lines, they lose their sensitivity to the cyanate metabolite. Chick fibroblasts which are normally insensitive to the cyanate metabolite become cyanate sensitive after transformation by the Schmidt-Ruppin strain of the Rous sarcoma virus.

Adenocarcinoma↗
PubMed1979

Antisickling agents: effects of carbamyl phosphate or cyanate on survival, erythrocytes, and leucocytes in the mouse.

Equal mole doses of the anions of disodium carbamyl phosphate (carbamyl P) or sodium cyanate, antisickling agents, have been compared in C57B1 mice. Using 15 mice per group, two groups were given the equivalent ip dose of carbamyl P or cyanate anion (7 mmoles/kg/day) in a divided dose, in the morning and six hours later, for 17--18 days. The control group received sodium chloride (13.8 mmoles of Na+ or Cl-/kg/day). Surviving mice per group were sodium chloride, 15/15; disodium carbamyl P, 14/15; and sodium cyanate, 0/15, all mice died by day 2. Surviving mice appeared normal throughout the study, and no abnormalities were seen at necropsy. The hematologic measurements were the same for sodium chloride or disodium carbamyl P, including hemoglobin, packed cell volume, erythrocyte counts, leucocyte counts, and differential counts. The mean hemoglobin carbamylation was 1.24 (+/- 0.06 SE) moles of valine hydantoin/mole of hemoglobin tetramer in mice receiving disodium carbamyl P for 18 days, sufficient for antisickling activity. The enzymatic degradation of carbamyl P to NH3, CO2, and Pi was measured in serial blood samples in additional C57B1 and DBA/2J mice following ip injections of carbamyl P or cyanate. Both NH3 and Pi increased immediately after giving carbamyl P, but no increase occurred after cyanate administration. Thus enzymatic degradation of carbamyl P occurs in vivo and appears to be an important detoxification mechanism. When equivalent mole doses of anion are administered, disodium carbamyl P is less toxic than sodium cyanate in mice.

Ammonia↗
PubMed1986

Effects of sodium cyanate in mice bearing B16 melanoma.

Sodium cyanate injected IP at a dose level of 200 or 250 mg/kg caused a 90% or greater inhibition of the incorporation of [3H]thymidine into DNA of B16 melanoma transplanted SC in mice. Despite the inhibitory effect of sodium cyanate on precursor incorporation into DNA, no significant effect on host survival was observed when sodium cyanate was administered as a single agent in the diet, in drinking water, or by IP injection to mice that had received IP transplants of B16 melanoma. The action of melphalan and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in prolonging the survival time of melanoma-bearing mice was not enhanced by combined treatment with sodium cyanate. However, combined injections of sodium cyanate and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) increased the survival of tumor-bearing mice significantly more than injections of BCNU alone at a lower dose than the maximum tolerated one. These data and other studies suggest that B16 melanoma may be less responsive to the action of sodium cyanate than are murine leukemic cells or rat hepatomas.

Animals↗
PubMed2003

Flow-injection spectrophotometric determination of cyanate in bioremediation processes by use of immobilised inducible cyanase.

A new flow injection (FI) method for photometric monitoring of cyanate in bioremediation processes using immobilised native cyanase is described. The method is based on the catalytic reaction between cyanate and bicarbonate to produce ammonia and carbon dioxide in the presence of an inducible native cyanase, immobilised in a reactor packed with glass beads. Two degrees of purification of the biocatalyst were used-heated cell-free extract and purified extract of cyanase from Pseudomonas pseudoalcaligenes CECT 5344. The ammonia produced by the enzymatic reaction is finally monitored photometrically at 700 nm using a modification of the conventional Berthelot method. The method furnishes different calibration curves depending on the degree of purification of the cyanase, with linear ranges between 1.23 and 616.50 micromol L(-1) ( r(2)=0.9979, n=7) and between 1.07 and 308.25 micro mol L(-1) ( r(2)= 0.9992, n=7) for the heated cell-free extract and the purified cyanase extract, respectively. No statistically significant differences between the samples were found in the precision study evaluated at two cyanate concentration levels using one-way analysis of variance. A sampling frequency of 15 h(-1) was achieved. The method was used to monitor cyanate consumption in a cyanate bioremediation tank inoculated with Pseudomonas pseudoalcaligenes CECT 5344 strain. The correlation between cyanate degradation and ammonia production was tested using a conventional method. Finally, the method was applied to different samples collected from the bioremediation tank using the standard addition method; recoveries between 85.9 and 97.4% were obtained.

Biodegradation, Environmental↗
PubMed1983

Inhibition by cyanate of the processing of lysosomal enzymes.

In cultured human fibroblasts, maturation of the lysosomal enzymes beta-hexosaminidase and cathepsin D is inhibited by 10 mM-potassium cyanate. In cells treated with cyanate the two enzymes accumulate in precursor forms. The location of the accumulated precursor is probably non-lysosomal; in fractionation experiments the precursors separate from the bulk of the beta-hexosaminidase activity. The secretion of the precursor of cathepsin D, but not that of beta-hexosaminidase precursor, is enhanced in the presence of cyanate. The secreted cathepsin D, as well as that remaining within the cells, contains mostly high-mannose oligosaccharides cleavable with endo-beta-N-acetylglucosaminidase H. After removal of cyanate, the accumulated precursor forms of the lysosomal enzymes are largely released from the pretreated cells. It is concluded that cyanate interferes with the maturation of lysosomal-enzyme precursors by perturbing their intracellular transport. Most probably cyanate affects certain functions of the Golgi apparatus.

Biological Transport↗
PubMed1971

Potassium cyanate as an inhibitor of the sickling of erythrocytes in vitro.

The recent use of urea as a treatment for the crisis phase of sickle-cell anemia has prompted us to investigate the possibility that cyanate, which is in equilibrium with urea in solution, might itself prevent the sickling of erythrocytes. We have found that in contrast to the high concentration of urea (1 M) needed to prevent reversibly the in vitro sickling of 80% of the cells, potassium cyanate (0.01-0.10 M) irreversibly inhibits sickling to the same extent. The prevention of sickling is a function of the amount of [(14)C]cyanate incorporated into acidprecipitable protein (0.1-1.0 mol of cyanate per mol of hemoglobin). Most of the radioactivity is accounted for by carbamylation of the NH(2)-terminal valine residues of hemoglobin; there is no detectable carbamylation of the lysine or cysteine residues. The reactive species, HN=C=O (isocyanic acid), may be an analog of O=C=O since both compounds bind to the same valine residues of hemoglobin. Deoxygenated sickled cells also incorporate [(14)C]-cyanate, but the sickling is not reversed. Oxygenation results in normal morphology in 75% of these cells. Upon subsequent deoxygenation, these cells remain normal. Potassium cyanate (5 mM) was also found to be an effective inhibitor of the gelling of deoxyhemoglobin S.

Anemia, Sickle Cell↗
PubMed1987

Cyanate specifically inhibits arginine biosynthesis in Escherichia coli K12: a case of by-product inhibition?

Growth of Escherichia coli K12 cultivated in minimal medium was strongly inhibited by 2 mM-cyanate. This inhibition could be specifically reversed by arginine. Citrulline (but not ornithine, N-alpha-acetylornithine or N-acetylglutamate) could also restore a normal growth rate. Since growth inhibition by cyanate was followed by an accumulation of ornithine within the cell it was concluded that cyanate specifically inhibits the formation of citrulline from ornithine. The effect of cyanate on the growth of defined strains was consistent with a specific inhibition of carbamoylphosphate synthase. A kinetic study of carbamoylphosphate synthase and ornithine carbamoyltransferase in vitro supported this conclusion. Since carbamoylphosphate is probably the only source of endogenous cyanate it is postulated that carbamoylphosphate synthase activity can be regulated by cyanate resulting from the dissociation of carbamoylphosphate in metabolic circumstances leading to its overproduction.

Arginine↗
PubMed1989

Cyanase-mediated utilization of cyanate in Pseudomonas fluorescens NCIB 11764.

Pseudomonas fluorescens NCIB 11764 was capable of utilizing cyanate (OCN-) as a sole nitrogen source for growth. Crude cell extracts from cells grown on cyanate, but not on ammonium sulfate, were induced for an enzyme catalyzing cyanate conversion to ammonia. Enzymatic activity was shown to be bicarbonate dependent and specific for cyanate as a substrate, suggesting that cyanate utilization in this organism is facilitated by an enzyme resembling cyanase (cyanate amidohydrolase; EC 3.5.5.3), as described previously in Escherichia coli and Flavobacterium sp.

Aminohydrolases↗
PubMed1989

Identification and characterization of a cyanate permease in Escherichia coli K-12.

Escherichia coli contains an inducible enzyme, cyanase, that catalyzes the decomposition of cyanate into ammonia and bicarbonate. The gene encoding cyanase, cynS, was cloned and found to be on a DNA fragment that contained the lac operon. Characterization of a plasmid encoding cyanase indicated that a 26-kilodalton (kDa) protein of unknown function was also induced by cyanate (Y-C. Sung, D. Parsell, P.M. Anderson, and J.A. Fuchs, J. Bacteriol. 169:2639-2642, 1987). The gene encoding the 26-kDa protein was located between cynS and its promoter, indicating the existence of a cyn operon. The 26-kDa protein was identified as a cyanate permease that transports exogenous cyanate by active transport. E. coli was shown to contain a cyanate transport system that is energy dependent and saturable by cyanate.

Aminohydrolases↗
PubMed1972

The effects of cyanate in vitro on red blood cell metabolism and function in sickle cell anemia.

Cyanate, which is in equilibrium with urea, combines with the alpha-amino group of the aminoterminal valine of hemoglobin in an irreversible, specific carbamylation reaction. Partial carbamylation (0.72 residues/hemoglobin tetramer) as determined by cyanate-(14)C incorporation or hydantoin analysis diminishes the in vitro sickling phenomenon. Since cyanate may react not only with hemoglobin but also with functional groups of other red blood cell proteins, the in vitro effect of cyanate was studied on sickle cells. Cells were incubated with 10 mM KCl (control) or 10 mM KNCO (carbamylated) for 1 hr, washed, and resuspended in autologous plasma. Glycolysis, ATP and 2,3-diphosphoglyceric acid (DPG) stability, autohemolysis, and osmotic fragility were not affected by carbamylation. Potassium loss in carbamylated cells (2.8 mmol/liter) was less than in control cells (9.0 mmol/liter). Pyruvate kinase activity of carbamylated cells was decreased ( approximately 25%) but the activities of other glycolytic enzymes were similar to those of control cells. Oxygen affinity of carbamylated sickle, normal, and DPG-depleted normal cells increased, and was a sensitive index of the degree and duration of reaction with cyanate. The reactivity of carbamylated cells to DPG was similar to control cells. DPG-depleted carbamylated cells regenerated DPG and increased the P(50) when incubated with pyruvate, inosine, and phosphate. The Bohr effect of normal and of sickle cells was not affected (Deltalog P(50)/Delta pH=-0.48 and -0.53, respectively) after carbamylation. The reserve buffering capacity of plasma offset the slightly diminished ( approximately 15%) CO(2) capacity of carbamylated cells so that whole blood CO(2) capacity, pH, and P(CO2) were normal. These studies provide further support for the potential clinical use of cyanate in treating and preventing the anemia and painful crises of sickle cell disease.

Adenosine Triphosphate↗
PubMed1988

Studies on metabolic pathways of cyanate in rats.

Metabolic pathways of cyanate in rats were studied by means of measurements of cyanate, carbamyl phosphate and S-carbamyl group. Approximately 30-50% of cyanate administered to rats (0.5 mmol/kg body weight) was found in buffered gastric contents, and was also detected as ammonia liberated by acid hydrolysis. However, the gastric excretion of cyanate was a temporary phenomenon just after cyanate administration. Biliary and urinary excretion of cyanate and acid-soluble S-carbamyl group are minor metabolic pathways.

Animals↗
PubMed1989

Interrelationship between sodium cyanate and pH in the regulation of tumor cell division.

Previous studies have suggested that the selective inhibitory effects of sodium cyanate on tumor metabolism in vivo may be related to a lower interstitial pH in tumors. In the present work, the influence of extracellular pH on the actions of sodium cyanate was studied with one rat hepatoma cell line (HTC) and two human colon tumor cell lines (HT29 and LS174T) and with rat hepatocytes to determine if the effects are accompanied by changes in intracellular pH. With some tumor cells, an inhibition of cell proliferation was observed when the cells were exposed to an acidic medium (pH 6.6). However, the LS174T line of human tumor cells divided at pH 6.6 essentially as fast as at pH 7.4. In the concentration range of 0.02-0.1 mg/ml, a greater inhibitory effect of cyanate on cell proliferation was observed at the lower pH. Intracellular pH was found to be influenced by the sodium ion concentration of the medium to a similar degree in the three tumor lines that were examined. The intracellular pH was found to be significantly affected by cyanate in rat hepatocytes and in two of the tumor cell lines (HT29 and LS174T). The data suggested that not only does extracellular pH influence the inhibitory effect of cyanate on tumor cell proliferation but also that cyanate can affect the regulation of intracellular pH in normal and neoplastic cells.

Animals↗