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PubMed2006

Indirect kinetic spectrophotometric determination of hydroxylamine based on its reaction with iodate.

A simple, precise and accurate method is proposed for rapid determination of trace amounts of hydroxylamine based on the reaction of hydroxylamine with iodate in acidic media. The reaction of neutral red by the produced nitrite ion was used to monitor the reaction spectrophotometrically at 525 nm by a fixed time method. Hydroxylamine in the range of 0.0400-1.200 microg mL(-1) could be determined. The relative standard deviation for 10 determinations of 0.500 microg mL(-1) hydroxylamine was 1.81% and the limit of detection was 0.010 microg mL(-1). The proposed method was applied to the determination of hydroxylamine in water samples with satisfactory results.

Alcohols↗

PubMed1999

Is hydroxylamine-induced cytotoxicity a valid marker for hypersensitivity reactions to sulfamethoxazole in human immunodeficiency virus-infected individuals?

Hypersensitivity (HS) reactions to sulfonamides and sulfones continue to limit their use in human immunodeficiency virus (HIV)-infected individuals. In vitro cytotoxicity of hydroxylamine metabolites toward peripheral blood mononuclear cells (PBMCs) has been proposed as a marker for these HS reactions. To test the validity of this in vitro system, we determined the selective susceptibility of PBMCs from HIV-infected patients to the cytotoxic effects of hydroxylamine metabolites of sulfamethoxazole (SMX) and dapsone (DDS). Concentration-cytotoxic response data were collected using PBMCs from 12 sulfa-HS (10 SMX-HS and 2 SMX/DDS-HS) and 10 sulfa-tolerant HIV-infected individuals. Although sulfamethoxazole hydroxylamine (SMX-NOH) and dapsone hydroxylamine (DDS-NOH) both caused concentration-dependent increases in cell death, DDS-NOH was significantly more potent in each subject (P <.0001). A comparison of a variety of mean data for sulfa-HS and -tolerant patient populations failed to demonstrate the increased susceptibility of PBMCs from HS patients, noted by others, to either SMX-NOH or DDS-NOH. Moreover, any trend toward an increased susceptibility of PBMCs from HS patients was eliminated when adjusted for control cell death. PBMCs from sulfa-HS patients showed significantly greater susceptibility to the stress of short term in vitro incubation (P <. 02). Mean (S.D.) vehicle control cell death values were 24.1% (7.6%) for HS patients and 17.1% (4.4%) for tolerant patients. No significant correlation was observed between hydroxylamine-induced or control cell death and any of the recorded clinical parameters. Although several potential reasons are proposed to explain the disparity with past investigations, the data suggest that in vitro cytotoxicity is not a valid marker for HS reactions in HIV-infected individuals using currently accepted experimental procedures.

Adult↗

PubMedDate not supplied

Hepatic microsomal metabolism of sulfamethoxazole to the hydroxylamine.

Sulfonamides are oxidized to protein reactive cytotoxic metabolites by murine hepatic microsomes. Mononuclear leukocytes from patients with idiosyncratic reactions to sulfonamides were more susceptible to toxicity from these metabolites than were leukocytes from a control population, suggesting that these metabolites play a role in the pathogenesis of such reactions. Here we have shown that murine hepatic microsomes oxidize sulfamethoxazole at the N4-position to form the hydroxylamine. Formation of the hydroxylamine was dependent on the presence of microsomes, NADPH, and oxygen. The addition of SKF 525-A, cimetidine, or gassing with carbon monoxide inhibited formation. The enzymic activity was stable at 37 degrees C in the absence of NADPH. Ascorbic acid, N-acetylcysteine, and reduced glutathione significantly increased the yield of hydroxylamine, presumably by decreasing further oxidation and covalent binding. Microsomes prepared from mice treated with phenobarbital or beta-naphthoflavone catalyzed the formation of the hydroxylamine more readily than did microsomes from untreated mice. These results demonstrate that cytochrome P-450-mediated oxidation of sulfamethoxazole results in the formation of hydroxylamines, which can be further oxidized to more reactive intermediates. These metabolites are likely involved in the pathogenesis of idiosyncratic reactions.

Animals↗

PubMedDate not supplied

Metabolism of procainamide to a hydroxylamine by rat and human hepatic microsomes.

We have previously demonstrated that procainamide is oxidized to a reactive metabolite. We speculated that this reactive metabolite might be a hydroxylamine and further that it might be responsible for the syndrome of procainamide-induced lupus. We now report that procainamide is metabolized to a hydroxylamine by rat and human hepatic microsomes. The extent of this metabolic oxidation was quantitated by HPLC after conversion of the hydroxylamine to the more stable nitro derivative of procainamide. Formation of the hydroxylamine required NADPH, active microsomes, and oxygen and was inhibited by carbon monoxide, SKF 525-A, and cimetidine. Formation of the hydroxylamine was also studied as a function of time, microsomal protein concentration, and procainamide concentration.

Adult↗

PubMed1975

[The mutagenic effect of new chemical substances. III. The mutagenic effect of several hydroxylamine derivatives].

The mutagenic effect of 21 new hydroxylamine derivatives was studied on biochemical mutants of Escherichia coli P-678 and Actinomyces rimosus 222. The Iver--Szybalsky method was used for the preliminary selection of mutagens. Dose-effect curves were plotted for the most efficient mutagens. Among the compounds studied 4 hydroxylamine derivatives were observed to have a mutagenic effect. The most efficient among them proved to be 0-(4-metoxybenzyl)-hydroxylamine and 0-(gamma-chlorocrotyl) hydroxylamine that induced reversions in the threonine locus of E. coli P-678 and in the lysine locus of Act. rimosus 222, being more efficient than hydroxylamine, the generally known mutagen. The dependence of the mutagenic activity of the compounds studied on their chemical structure is investigated.

Escherichia coli↗

PubMed1998

The effect of cimetidine on the formation of sulfamethoxazole hydroxylamine in patients with human immunodeficiency virus.

Hypersensitivity reactions from trimethoprim/sulfamethoxazole are likely caused by a reactive nitroso intermediate formed from sulfamethoxazole hydroxylamine. This pilot study tested whether cimetidine inhibits the urinary excretion of sulfamethoxazole hydroxylamine. Ten outpatients infected with human immunodeficiency virus (HIV) and currently receiving trimethoprim/sulfamethoxazole prophylaxis were randomly selected from 59 eligible patients. Five received cimetidine 800 mg twice daily for 1 week and five served as controls. Two spot urine samples one week apart were obtained after a trimethoprim/sulfamethoxazole dose for all patients. Patients taking cimetidine had a significant decrease in excretion of sulfamethoxazole hydroxylamine relative to total excreted drug in the two urine samples compared with control patients. Cimetidine likely caused this decrease in sulfamethoxazole hydroxylamine excretion through inhibition of CYP3A4. Because of potential differences between HIV-infected patients and healthy subjects in oxidative metabolism, future studies of inhibitors of sulfamethoxazole hydroxylamine formation should be conducted in the HIV population.

Adult↗

PubMed1994

Reduction of dapsone hydroxylamine to dapsone during methaemoglobin formation in human erythrocytes in vitro. IV: Implications for the development of agranulocytosis.

We have studied the efflux of dapsone hydroxylamine from normal and diabetic erythrocytes by the use of a two-compartment (1 and 2) in vitro dialysis system, in order to model the in vivo blood supply to the bone marrow. When both types of erythrocytes were dialysed against mononuclear leucocytes, the hydroxylamine crossed the membrane and caused significantly greater white cell death compared with dialysis of leucocytes against untreated erythrocytes. However, in the case of both normal and diabetic cells, the presence of the glutathione depletor diethyl maleate (DEM) caused a marked reduction in movement of hydroxylamine from compartment 1 to 2. Diethyl dithiocarbamate (DDC), a methaemoglobin accelerant, caused a marked reduction in movement of hydroxylamine from erythrocytes (diabetic and normal) in compartment 1 to 2 which led to a significant reduction in white cell death compared with the absence of DDC (18.3 +/- 5.5 vs 34.8 +/- 8.1%, P < 0.05). Dapsone recovery from compartment 1 rose significantly in the presence of DDC compared with control in both erythrocyte types. In contrast, recovery of dapsone from normal erythrocytes incubated in compartment 1 was significantly reduced by the presence of DEM compared with control, although there was no difference between control and DEM-treated diabetic cells. Dapsone analysis in compartment 2 revealed a significant increase in dapsone recovery in both diabetic (11.3 +/- 1.1%) and normal (11.9 +/- 1.1%) erythrocytes in the presence of DDC compared with diabetic (3.3 +/- 0.4%) and normal control (4.8 +/- 2.0%, P < 0.001). The presence of DEM in compartment 1 caused a significant fall in dapsone recovery in compartment 2 (3.7 +/- 0.26) compared with control (4.7 +/- 0.36%, P < 0.05). Hence, dapsone hydroxylamine is capable of leeching out of normal and diabetic erythrocytes, traversing a semipermeable membrane and causing toxicity to human mononucleocyte cells in vitro. This process may be one of the first stages in immune-mediated agranulocytosis.

Agranulocytosis↗

PubMed2005

Oxidation of hydroxylamine by nitrous and nitric acids. Model development from first principle SCRF calculations.

Ab initio molecular orbital calculations have been performed to develop an elementary reaction mechanism for the autocatalytic and scavenging reactions of hydroxylamine in an aqueous nitric acid medium. An improved understanding of the titled reactions is needed to determine the "stability boundary of hydroxylamine" for safe operations of the plutonium-uranium reduction extraction (PUREX) process. Under the operating conditions of the PUREX process, namely, 6 M nitric acid, the reactive forms of hydroxylamine are NH2OH, NH3OH+, and the complex NH3OH.NO3, and those of nitrous acid are NO+, H2ONO+, N2O4, N2O3, NO2, and NO. High-level CBSQB3/IEFPCM and CBSQB3/COSMO calculations were performed using GAUSSIAN03 to investigate the energy landscape and to explore a large number of possible ion-ion, ion-radical, ion-molecule, radical-radical, radical-molecule, and molecule-molecule pathways available to the reactive forms of the reactants in solution. It was found that in solution the autocatalytic generation of nitrous acid proceeds through free radical pathways at low-hydroxylamine concentrations from unprotonated NH2OH via hydrogen abstraction. At high [NH3OH+], we suggest a possible involvement of the NH3ONO+ intermediate via the reaction NH2ONO + NO2 --> HNO + HONO + NO. The NH3ONO+ intermediate, in turn, is formed favorably via the ion-ion reactions of NH3OH+ with NO+ and/or the reaction between NO+ and hydroxylammonium nitrate (HAN). The intermediates involved in the scavenging reaction of nitrous acid by hydroxylamine are NH3ONO+, NH2ONO, NH2(NO)O, NH(NO)OH, and HONNOH and the rate-determining step is the 1,2-NO migration in NH2ONO leading to NH2(NO)O. Reactions NH2ONO --> NH2(NO)O and NH2(NO)O --> NH(NO)OH were studied with two explicit water molecules and the results are discussed in the context of the importance of the explicit treatment of solvent in the determination of the energetics and mechanism of these processes. The rate constants for the reactions were estimated using transition-state theory and other traditional techniques. The kinetic parameters obtained at the B3LYP/CBSB7/IEFPCM level are in reasonable agreement with the limited experimental value. IEFPCM results on free energy of undelocalized polar ions such as NO3-, NO2-, and NH3OH+ are not very accurate and have difficulties in predicting the right direction of acid dissociation equilibrium of HONO2, HONO, and NH3OH+. Explicit incorporation of a solvation shell to these ions improves the theoretical descriptions of acid ionization equilibria as it captures some of the nonlocal effects of these ions. Additional work is needed to correctly describe the solvation shell and to introduce consistency in the theoretical treatment involving explicit solvent molecules. Nevertheless, this systematic exploration of reactions in solution and mechanism development for a solution phase process based on self-consistent reaction field (SCRF) results is likely to be one of the first of its kind.

Journal Article↗

PubMed1995

Dapsone-induced hemolytic anemia: effect of dapsone hydroxylamine on sulfhydryl status, membrane skeletal proteins and morphology of human and rat erythrocytes.

Dapsone hydroxylamine is a direct-acting hemolytic agent responsible for dapsone-induced hemolytic anemia in the rat. In the present study, we compared the responsiveness of rat and human red cells to dapsone hydroxylamine-induced cellular changes. Dapsone hydroxylamine induced a rapid and concentration-dependent loss of erythrocytic reduced glutathione content with a concomitant increase in protein-glutathione mixed disulfide formation in both human and rat red cell suspensions. However, the rate of mixed disulfide formation in human cells was considerably slower than that in rat cells and was preceded by a transient increase in oxidized glutathione (glutathione disulfide) formation. Sodium dodecylsulfate-polyacrylamide gel electrophoresis and immunoblotting analysis of membrane ghosts from human red cells revealed changes in skeletal proteins that in general were similar to those observed with rat cells, including a loss of protein band 2.1 and the appearance of membrane-bound hemoglobin. Notable differences were the resistance to loss of band 4.2 and a considerably higher amount of protein aggregation in human ghosts. Although the morphology of human red cells was altered, the incidence and degree of change were considerably less than those of rat red cells. Furthermore, the concentration of dapsone hydroxylamine required to induce damage in human red cells (175-750 microM) was significantly higher than that required for rat red cells (50-175 microM), suggesting that human cells are probably less sensitive than rat cells to dapsone hydroxylamine-induced oxidative damage.

Anemia, Hemolytic↗

PubMed1984

Hypotensive effects of hydroxylamine in intact anesthetized dogs and cats.

When given IV in bolus doses to intact anesthetized dogs or cats, hydroxylamine hydrochloride produced transient but precipitous falls in the mean arterial blood pressure in a dose-related manner, as well as a significant methemoglobinemia. The half-time for recovery of the mean arterial pressure was also dose-related. These effects were very similar to those elicited by comparable doses of sodium nitrite, except that the half-recovery time for return to normal blood pressure was somewhat longer with nitrite. Although hydroxylamine has long been known to relax vascular smooth muscle in vitro, we are not aware of previous demonstrations of hypotensive effects in vivo. Acute poisoning by either nitrite or hydroxylamine is apt to result in both an anemic hypoxia due to methemoglobinemia and a stagnat (hypokinetic) hypoxia due to direct vasodilation. Hydroxylamine, but not nitrite, also appeared to stimulate respiration possibly through an effect on the chemoreceptors of the carotid body.

Anesthesia↗

PubMed1984

CU(II)-dependent inactivation of Mn-catalase by hydroxylamine.

Hydroxylamine is a strong inhibitor of the Mn-catalase of Lactobacillus plantarum in the presence of hydrogen peroxide [Kono, Y., and Fridovich, I. (1983) J. Biol. Chem. 258, 13646-13648]. In the presence of CuCl2 the Mn-catalase was rapidly inactivated by hydroxylamine without the addition of hydrogen peroxide. FeSO4 and MnCl2 were approximately 10% and 4% as effective as was CuCl2. Under anaerobic conditions, the inactivation did not occur. The chelating agents such as EDTA and histidine completely prevent the inactivation. These results indicate that the hydrogen peroxide produced during the autooxidation of hydroxylamine catalyzed by CuCl2 participates in the CuCl2-dependent inactivation by hydroxylamine.

Anaerobiosis↗

PubMed1993

Effects of hydroxylamine, digitonin and triton X-100 on photoreceptor (paraflagellar swelling) and photoreception of Euglena gracilis.

We present experiments that test the effects of agents commonly used in visual pigment investigations, namely hydroxylamine (NH2OH), digitonin and triton X-100, on the photoreceptor and photoreception of Euglena. Hydroxylamine reacts with free and opsin-bound retinal, in aqueous solution, to form stable oximes, whereas digitonin and triton X-100 are the most common extractants of rhodopsin. Since previous data indicate that the chromophore present in Euglena photoreceptor is retinal, we investigated the influence of these chemicals on this organelle. The effects of these agents were studied by means of phase contrast, fluorescence and transmission electron microscopy and photobehaviour experiments. Hydroxylamine inhibited the formation of the Euglena photoreceptor. Photoaccumulation experiments on hydroxylamine-treated cells showed that they are unable to perceive light. Digitonin solubilized the crystalline structure of the photoreceptor, whereas the triton effect was limited to the membranous structures of the cell, leaving the photoreceptor unimpaired.

Animals↗

PubMed1996

Hydroxylamine and phenol-induced formation of methemoglobin and free radical intermediates in erythrocytes.

As previously shown with isolated oxyhemoglobin, methemoglobin formation can also be induced in intact erythrocytes by hydroxylamine compounds and substituted phenols such as butylated hydroxyanisole (BHA). Electron spin resonance investigations revealed that, accordingly, free radical intermediates were formed in erythrocytes from hydroxylamine, N,N-dimethylhydroxylamine, and N-hydroxyurea. Due to the low stability of the dihydronitroxyl radicals, their detection required the use of a continuous flow system and relatively high amounts of the reactants. As has already been demonstrated with the solubilized hemoglobin system, hemoglobin of intact erythrocytes also reacts with the more hydrophilic xenobiotics such as hydroxylamine. However, the reaction rate was slightly reduced, indicating the existence of an incomplete permeability barrier for these compounds. The limited solubility of phenolic compounds in the aqueous buffer of suspended erythrocytes (in combination with the strict requirement of osmolarity in order to prevent hemolysis) impeded the direct detection of the respective phenoxyl radicals previously reported in hemoglobin solutions. However, in accordance with earlier findings in homogeneous reaction systems, chemiluminescence was observed as well, indicating the existence of a further reaction intermediate, which was also obtained in pure hemoglobin solutions when mixed with the respective reactants. As has recently been demonstrated, this light emission is indicative of the existence of highly prooxidative compound I intermediates during methemoglobin formation. Prooxidant formation in erythrocytes is reflected by a significant decrease in thiol levels even with those compounds where free radical formation was not directly detectable by ESR spectroscopy. The use of the spin-labeling technique revealed membrane effects as a result of oxidative stress. Oxidative metabolism of hemoglobin with hydroxylamine caused a release of low molecular weight iron. The marked hemolysis observed in the presence of BHA results from a direct membrane effect of this compound rather than a consequence of free radical-induced oxidative stress. A correlation of the different results is discussed in terms of possible toxicological consequences.

Animals↗

PubMed1984

N-hydroxycarbamate is the substrate for the pyruvate kinase catalyzed phosphorylation of hydroxylamine.

The true substrate for the pyruvate kinase catalyzed phosphorylation of hydroxylamine at high pH which is activated by bicarbonate is shown to be N-hydroxycarbamate, since a lag is seen when the reaction is started by the addition of bicarbonate or hydroxylamine but a burst appears when it is started with a mixture of the two. The lag can be diminished by addition of carbonic anhydrase but not eliminated, showing that CO2 is an intermediate in the formation of the carbamate and that both the formation of CO2 and the subsequent reaction of CO2 with hydroxylamine limit the rate of carbamate formation. The equilibrium constant for the reaction bicarbonate + hydroxylamine reversed N-hydroxycarbamate is 1.33 M-1. The product of the phosphorylation decomposes by loss of CO2 to O-phosphorylhydroxylamine, which is stable at 25 degrees C between pH 3 and 11 and has pK2 = 5.63 for the phosphate and pK3 = 10.26 for the amino group.

Bicarbonates↗

PubMed1993

Hydrazine and hydroxylamine as probes for O2-reduction site of mitochondrial cytochrome c oxidase.

Reactions of hydrazine and hydroxylamine with bovine heart cytochrome c oxidase in the fully reduced state were investigated under anaerobic conditions following the visible-Soret spectral change. Hydrazine gave a sharp band at 575 nm with 20% decrease in the alpha band at 603 nm, and hydroxylamine induced a 2 nm blue-shift for the alpha band without any clear splitting. The Soret band at 443 nm was decreased significantly in intensity, with the concomitant appearance of a shoulder with hydrazine or a peak with hydroxylamine, both near 430 nm. The dependence on pH of the affinity of these reagents for the enzyme indicates that only the deprotonated forms of these reagents bind to the enzyme, suggesting a highly hydrophobic environment of the haem ligand-biding site. These spectral changes were largely removed by addition of cyanide or CO. However, detailed analysis of these spectral changes indicates that hydrazine perturbs the shape of the spectral change induced by cyanide and hydroxylamine perturbs that induced by CO. These results suggest that these aldehyde reagents bind to haem a3 iron as well as to a second site which is most likely to be the formyl group on the haem periphery, and that these two sites bind these reagents anti-cooperatively with each other.

Animals↗

PubMed1997

Paracatalytic inactivation of L-2-haloacid dehalogenase from Pseudomonas sp. YL by hydroxylamine. Evidence for the formation of an ester intermediate.

Asp10 of L-2-haloacid dehalogenase from Pseudomonas sp. YL was proposed to act as a nucleophile to attack the alpha-carbon of L-2-haloalkanoic acids to form an ester intermediate, which is hydrolyzed by nucleophilic attack of a water molecule on the carbonyl carbon (Liu, J.-Q, Kurihara, T., Miyagi, M., Esaki, N., and Soda, K. (1995) J. Biol. Chem. 270, 18309-18312). We have found that the enzyme is paracatalytically inactivated by hydroxylamine in the presence of the substrates monochloroacetate and L-2-chloropropionate. Ion spray mass spectrometry demonstrated that the molecular mass of the enzyme inactivated by hydroxylamine during the dechlorination of monochloroacetate is about 74 Da greater than that of the native enzyme. To determine the increase of the molecular mass more precisely, we digested the inactivated enzyme with lysyl endopeptidase and measured the molecular masses of the peptide fragments. The molecular mass of the hexapeptide Gly6-Lys11 was shown to increase by 73 Da. Tandem mass spectrometric analysis of this peptide revealed that the increase is due to a modification of Asp10. When the enzyme was paracatalytically inactivated by hydroxylamine during the dechlorination of L-2-chloropropionate, the molecular mass of the hexapeptide was 87 Da higher. Hydroxylamine is proposed to attack the carbonyl carbon of the ester intermediate and form a stable aspartate beta-hydroxamate carboxyalkyl ester residue in the inactivated enzyme.

Acetates↗

PubMed1997

Nitric oxide generation from sodium nitroprusside and hydroxylamine in brain.

We aimed to demonstrate different modes of in situ nitric oxide (NO) generation from two NO donors in cerebral cortex of halothane anesthetized cats. NO donors were delivered by in vivo microdialysis into the cortical tissue where an NO electrode measured real-time changes in extracellular NO concentration. In vitro testing in Finger's solution revealed that sodium nitroprusside (SNP) liberates NO spontaneously in the presence of light, whereas hydroxylamine does not generate any NO under these conditions. Supplementation with 200 mM of the NO donors SNP and hydroxylamine evoked dose-related increases in NO concentration (52.0 +/- 6.7 nM, n = 5, and 14.0 +/- 3.8 nM, n = 5, respectively). The increase in NO concentration was significantly greater during SNP than during hydroxylamine delivery (p < 0.001). In contrast, CBF increased similarly under the influence of both NO donors. Electrocorticogram and cortical direct current potential remained unaffected. In conclusion, hydroxylamine is degraded into NO intracellularly and efficiently dilates cerebral blood vessels. SNP, in contrast, generates NO mainly in the extracellular space.

Animals↗

PubMed1993

Vasodilator effects of hydroxylamine in the isolated rodent lung.

Hydroxylamine is a natural product of cellular metabolism that possesses vasodilating properties similar to those of endothelium-derived relaxing factor (EDRF). In the rodent pulmonary circulation preconstricted with the endoperoxide analog U-46619, hydroxylamine relaxed the vasculature in a concentration-dependent manner. Blockade of the hydroxylamine vasodilator response by methylene blue indicated that the mechanism of vasorelaxation is similar to that of EDRF. In this preparation, hydroxylamine is a more potent vasodilator than nitroglycerin.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗