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PubMed1977

Opposite effect of organic phosphates on hemoglobin oxidation by hydroxylamine under aerobic and anaerobic conditions.

The effect of organic phosphates such as inositol hexaphosphate (IHP), ATP, and 2,3-diphosphoglycerate (2,3-DPG) on hemoglobin oxidation by hydroxylamine was studied under aerobic and anaerobic conditions. Under aerobic conditions, the oxidation rate of hemoglobin by hydroxylamine was accelerated as much as about 1.6 times, 1.4 times, and 1.4 times in the presence of IHP, ATP, and 2,3-DPG, respectively; however, under anaerobic conditions it was inhibited as much as 2.2 times, 2 times, and 2 times in the presence of these organic phosphates compared with the case for the absence of these organic phosphates. The effects of these organic phosphates on hemoglobin oxidation by hydroxylamine under aerobic conditions were elucidated by the two state models of hemoglobin including the R and the T state, however, the opposite effects under anaerobic conditions cannot be explained without the assumption of the existence of a third conformation of hemoglobin. The dissociation constant of IHP to deoxyhemoglobin was estimated from the rate of the hemoglobin oxidation by hydroxylamine in different concentrations of IHP under anaerobic conditions.

Adenosine Triphosphate↗
PubMed1976

Protection by GABA and succinic semialdehyde of seed germination and some enzymatic activities against high concentration of hydroxylamine.

Hydroxylamine was found to stimulate germination of Lupinus albus at concentrations inferior to 10 mM and to inhibit it greatly at 20 mM concentration. This inhibition was partially restored by GABA or succinic semialdehyde. Hydroxylamine, at high concentrations, behaved as inhibitor in vivo on GABA 2-oxyglutarate amino-transferase and succinic semialdehyde dehydrogenase NAD-dependent, whereas it behaved as activator on succinic semialdehyde dehydrogenase NADP-dependent. No effects were observed on the enzymatic activities and the inhibited germination was partially restored, after GABA and succinic semialdehyde had been added to a growth medium with a 20 mM hydroxylamine concentration. A possible protection mechanism of GABA and succinic semialdehyde against hydroxylamine action is discussed.

Aminobutyrates↗
PubMed1965

MUTAGENIC EFFECTS OF HYDROXYLAMINE IN VIVO.

Hydroxylamine can induce any one of the four types of transition mutations in bacteriophage S13 if the mutagen is added directly to agar plates seeded with phage and bacterial indicators. The phage can also be mutated by treating the host cell with hydroxylamine before infecting it with phage. These effects of hydroxylamine in vivo contrast with the mutagenic effect in vitro, which seems to be exclusively on cytosine.

Bacteriophages↗
PubMed1995

Metabolism of dapsone to its hydroxylamine by CYP2E1 in vitro and in vivo.

Dapsone toxicity is putatively initiated by formation of a hydroxylamine metabolite by cytochromes P450. In human liver microsomes, the kinetics of P450-catalyzed N-oxidation of dapsone were biphasic, with the Michaelis-Menten constants of 0.14 +/- 0.05 and 0.004 +/- 0.003 mmol/L and the respective maximum velocities of 1.3 +/- 0.1 and 0.13 +/- 0.04 nmol/mg protein/min (mean +/- SEM). Troleandomycin (40 mumol/L) inhibited hydroxylamine formation at 100 mumol/L dapsone by 50%; diethyldithiocarbamate (150 mumol/L) and tolbutamide (400 mumol/L) inhibited at 5 mumol/L dapsone by 50% and 20%, respectively, suggesting that the low-affinity isozyme is CYP3A4 and the high-affinity isozymes are 2E1 and 2C. Disulfiram, 500 mg, 18 hours before a 100 mg oral dose of dapsone in healthy volunteers, diminished area under the hydroxylamine plasma concentration-time curve by 65%, apparent formation clearance of the hydroxylamine by 71%, and clearance of dapsone by 26%. Disulfiram produced a 78% lower concentration of methemoglobin 8 hours after dapsone.

Adult↗
PubMed1992

Suppression of T-lymphocyte proliferation by sulphonamide hydroxylamines.

Hypersensitivity adverse drug reactions, characterized by fever and multi-organ involvement, are the most severe adverse reactions to sulphonamides. Although there is evidence that these reactions are initiated by metabolic events, these reactions appear to be propagated on an immune basis. We investigated the effect of a sulphonamide reactive metabolite, the hydroxylamine of sulphamethoxazole (SMX H/A), on the ability of T-lymphocytes to respond to stimulation with mitogens. Peripheral blood mononuclear cells (PBMCs) were collected and incubated with SMX H/A in increasing concentrations. PBMCs were then incubated with phytohaemagglutinin (PHA) and phorbol myristate acetate (PMA) or with PHA and ionomycin. T-lymphocyte proliferation was then determined by tritiated thymidine uptake. The hydroxylamine of sulphamethoxazole produced a concentration-dependent decrease in T-lymphocyte proliferation; this decrease was significant even at concentrations of hydroxylamine that were not associated with a decrease in cell viability. PBMCs incubated with SMX H/A that were washed and then added to fresh PBMCs failed to inhibit the proliferation of fresh PBMCs. The hydroxylamine of sulfamethoxazole produces profound suppression of T-lymphocyte proliferation. This suppression appears to be a direct event and does not involve the activation of suppressor cells. These findings may explain the infectious complications contributing to mortality associated with sulphonamide hypersensitivity reactions.

Cell Survival↗
PubMed1995

Suicide inactivation of hydroxylamine oxidoreductase of Nitrosomonas europaea by organohydrazines.

In the presence of a suitable electron acceptor such as mammalian cytochrome c, hydroxylamine oxidoreductase (HAO) from the chemolithotrophic bacterium Nitrosomonas europaea catalyzes the oxidation of hydroxylamine or hydrazine to nitrite or dinitrogen, respectively. Each subunit of HAO contains 7 c-hemes and a chromophore of the active site called heme P460, a c-heme bridged from a methylene carbon to a ring carbon of a tyrosine of the peptide chain. Reaction with either substrate results in reduction of several c-hemes of HAO. The reaction of organohydrazines with HAO was investigated in this work. HAO was inactivated by (phenyl-, (methyl-, or (hydroxyethyl)hydrazine. The process followed first order kinetics and was inhibited by the substrates, hydroxylamine or hydrazine. Complete loss of enzyme activity and absorbancy characteristic of native heme P460 of HAO occurred at a 1:1 ratio of phenylhydrazine and HAO. HAO was covalently derivatized by two molecules of [14C]-phenylhydrazine per subunit. Heme P460 was derivatized with high affinity, and an amino acid residue was derivatized with lower affinity. c-Hemes were not derivatized except for the partial reaction of (hydroxyethyl)hydrazine with one heme. As with hydroxylamine and hydrazine, incubation with organohydrazines resulted in reduction of c-heme of HAO. Derivatized minus native optical difference spectra of ferric or ferrous HAO revealed changes in the optical properties of heme P460 which were generally similar to shifts seen in the reaction of the heme of other hemoproteins with organohydrazines.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding Sites↗
PubMed2003

Hydroxylamines as oxidation catalysts: thermochemical and kinetic studies.

Bond dissociation enthalpies (BDE) of hydroxylamines containing alkyl, aryl, vinyl, and carbonyl substituents at the nitrogen atom have been determined by using the EPR radical equilibration technique in order to study the effect of the substituents on the O-H bond strength of these compounds. It has been found that substitution of an alkyl group directly bonded to the nitrogen atom with vinyl or aryl groups has a small effect, while substitution with acyl groups induces a large increase of the O-H BDE value. Thus, dialkyl hydroxylamines have O-H bond strengths of only ca. 70 kcal/mol, while acylhydroxylamines and N-hydroxyphthalimide (NHPI), containing two acyl substituents at nitrogen, are characterized by BDE values of ca. 80 and 88 kcal/mol, respectively. Since the phthalimide N-oxyl radical (PINO) has been recently proposed as an efficient oxidation catalyst of hydrocarbons or other substrates, the large BDE value found for the parent hydroxylamine (NHPI) justifies this proposal. Kinetic studies, carried out in order to better understand the mechanism of the NHPI-catalyzed aerobic oxidation of cumene, are consistent with a simple kinetic model where the rate-determining step is the hydrogen atom abstraction from the hydroxylamine by cumylperoxyl radicals.

Journal Article↗
PubMed1992

Sulfamethoxazole is metabolized to the hydroxylamine in humans.

The oxidation of sulfamethoxazole to its hydroxylamine metabolite was investigated in vitro with human liver microsomes and in vivo by detection in the urine. Sulfamethoxazole was oxidized to the hydroxylamine in an NADPH-dependent process by liver microsomes prepared from two human livers. Three healthy volunteers ingested 1000 mg sulfamethoxazole, and urine was collected for 24 hours. Sulfamethoxazole hydroxylamine constituted 3.1% +/- 0.7% of the drug excreted in the urine in 24 hours. Fifty-four percent of the ingested dose was excreted during this same time period. We conclude that sulfamethoxazole hydroxylamine is an authentic in vivo metabolite in humans, probably formed predominantly by cytochrome P450 in the liver. It could be responsible for mediation of sulfonamide adverse reactions, particularly hypersensitivity reactions.

Adult↗
PubMed1996

The biochemical characterization of a novel non-haem-iron hydroxylamine oxidase from Paracoccus denitrificans GB17.

The characterization of the hydroxylamine oxidase from the heterotrophic nitrifier Paracoccus denitrificans GB17 indicates the enzyme to be entirely distinct from the hydroxylamine oxidase from the autotrophic nitrifier Nitrosomonas europaea. Hydroxylamine oxidase from P. denitrificans contains three to five non-haem, non-iron-sulphur iron atoms as prosthetic groups, predominantly co-ordinated by carboxylate ligands. The interaction of the enzyme with the electron-accepting proteins cytochrome C556 and pseudoazurin is mainly hydrophobic. The catalytic mechanism of hydroxylamine oxidase from P. denitrificans is different from the enzyme from N. europaea because the production of nitrite by the former requires molecular oxygen. Under anaerobic conditions the enzyme makes nitrous oxide as a sole product.

Edetic Acid↗
PubMed2000

NADH-dependent reduction of sulphamethoxazole hydroxylamine in dog and human liver microsomes.

1. Reduction of hydroxylamine drug metabolites by NADH-dependent hydroxylamine reductase (NDHR) has been suggested to be involved in the pathogenesis of idiosyncratic sulphonamide toxicity in humans. The dog represents a naturally occurring clinical model for sulphonamide toxicity in humans. he purpose of these studies, therefore, was to characterize the presence of hepatic NADH-dependent hydroxylamine reductase activity in the dog and to compare this activity with that found in humans. 2. NDHR activity was characterized by the presence of two enzymes in both dog and human liver microsomes, with comparable estimates of Km (Km1 = 75 microM, Km2 = 404 microM in dog; Km1 = 69 microM, Km2 = 503 microM in human). Estimates of maximal velocity were significantly, but not dramatically, higher for dog NDHR (Vmax1 = 2.09 nmole mg(-1) min(-1) Vmax2 = 4.58 nmole mg(-1) min(-1) compared with human NDHR (Vmax1 = 0.42 nmole mg(-1) min(-1), Vmax2 = 1.56 nmole mg(-1) min(-1)). NDHR in dog, as in humans, preferred NADH to NADPH, was more active at pH 6.3 than at 7.4 and was not inhibited by carbon monoxide, azide, anaerobic conditions, the CYP substrate inhibitors tolbutamide, dextromethorphan, or erythromycin, or antibodies directed against CYP2C, CYP2D or CYP3A. 3. It is concluded that two forms of NDHR are present in dog and humans with similar biochemical characteristics. Although NDHR activity has been attributed to a CYP2D isoform in pig, there is no evidence for involvement of CYP450 in the reduction of sulphamethoxazole hydroxylamine in either dogs or humans.

Adult↗
PubMed1996

The effect of acetylation and deacetylation on the disposition of dapsone and monoacetyl dapsone hydroxylamines in human erythrocytes in-vitro.

The fates of both dapsone and monoacetyl hydroxylamine have been studied in terms of acetylation and deacetylation within the human erythrocyte in-vitro. A comparison between the two metabolites showed equipotency in methaemoglobin generation at 15 min, although the monoacetyl derivative was the more rapid haemoglobin oxidizer. Within the erythrocytes, both dapsone and monoacetyl hydroxylamines were found to undergo acetylation, deacetylation and diacetylation. Of the inhibitors of acetylation studied, folate caused an increase in methaemoglobin formation associated with both metabolites, which led to a rise in both acetylated and non-acetylated amine formation. Amethopterin was associated with a rise in hydroxylamine mediated methaemoglobin formation which coincided with a fall in acetylated products. It is possible that the hydroxylamines undergo erythrocytic processes of acetylation and deacetylation before methaemoglobin-mediated reduction to their respective amines.

Acedapsone↗
PubMed1992

Cytochrome P-455 nm complex formation in the metabolism of phenylalkylamines. XIII. Enzyme interactions with a series of beta-alkyl-substituted 2-phenylethanamines and corresponding N-hydroxylamines.

The formation of Metabolic Intermediate (MI) complexes from a series of beta-alkylsubstituted 2-phenylethanamines and corresponding N-hydroxylamines is investigated during NADPH-dependent metabolism in liver microsomes from phenobarbital pretreated rats. The beta-alkyl substituents are methyl, dimethyl, ethyl, di-ethyl, n-propyl, di-n-propyl and i-propyl groups. The amines are synthesized by LiAlH4-reduction of the corresponding nitriles, which are prepared through alkylation of the enolate anion of phenylacetonitrile. The hydroxylamines are prepared either by oxidation of the corresponding benzylimines with m-chloroperbenzoic acid and subsequent hydrolysis of the initially formed 3-phenyloxaziridines, or by H2O2-mediated oxidation of the corresponding amines in the presence of catalytic amounts of sodium tungstate, followed by reduction with cyanoborohydride. The amines are found to be completely devoid of complexing activity, while the hydroxylamines form the MI complex at high rates. Complex formation from these substrates thus parallels the known behaviour of 2-phenylethanamine and its corresponding N-hydroxylamine. Since N-oxygenation is known to be a prerequisite for MI complex formation from amines our results suggest that the beta-alkylated 2-phenylethanamines are metabolized exclusively through other pathways. In accordance with this hypothesis, capillary GC-analysis of the incubation mixture of 2-phenylpropanamine shows no formation of N-hydroxylated metabolites; only 2-phenylpropanol, a metabolite formed through the deamination pathway, is found.

Amines↗
PubMed1984

Mössbauer, EPR, and optical studies of the P-460 center of hydroxylamine oxidoreductase from Nitrosomonas. A ferrous heme with an unusually large quadrupole splitting.

Hydroxylamine oxidoreductase from Nitrosomonas europeae catalyzes the oxidative conversion of NH2OH to NO-2. The enzyme, Mr = 220,000, has an (alpha beta)3 subunit structure with each alpha beta subunit containing 7-8 c-type hemes and one unusual prosthetic group, termed P-460. The P-460 is also found in a Mr approximately equal to 17,000 protein (P-460 fragment). Mössbauer spectra of the reduced P-460 groups, in hydroxylamine oxidoreductase and the fragment, exhibit nearly identical quadrupole doublets with an unusually large splitting, delta EQ = 4.21 mm/s (no ferrous heme protein is known with delta EQ greater than 2.75 mm/s). The observed isomer shift, delta = 0.96 mm/s at 4.2 K, shows that the P-460 iron is high spin ferrous. Treatment of oxidized hydroxylamine oxidoreductase with H2O2 followed by reduction or exposure of the native sample to CO led to the disappearance of both the characteristic 460 nm absorption band (epsilon = 89 mM-1 cm-1) and the delta EQ = 4.21 mm/s doublet. The iron of the oxidized P-460 fragment is high spin ferric, with Mössbauer and EPR parameters very similar to those of metmyoglobin. Optical spectra of the reduced P-460 fragment show long wavelength bands at 650 and 688 nm which are sensitive to treatment of the fragment with reagents which react with P-460. These bands were, however, not detected in hydroxylamine oxidoreductase. The spectroscopic and chemical evidence obtained to date suggests strongly that the P-460 iron resides in a heme-like macrocycle although the presumed porphyrin must have some unusual features.

Electron Spin Resonance Spectroscopy↗
PubMed1993

Hydroxylamine oxidoreductase from Nitrosomonas europaea is a multimer of an octa-heme subunit.

A fully active form of hydroxylamine oxidoreductase from Nitrosomonas has been purified with high recovery and shown by reverse-phase high performance liquid chromatography and N-terminal analysis to contain only a 63-kDa subunit and to lack the 11-kDa protein previously thought to be a second subunit. Based on the previously published values of molecular weight in solution, hydroxylamine oxidoreductase probably has an alpha 2 or alpha 3 oligomeric structure. The enzyme was digested separately with trypsin and chymotrypsin and peptides which contained covalently bound heme were separated by high performance liquid chromatography and their amino acid sequences determined. A total of seven heme-containing peptides of unique amino acid sequence were obtained. Six of these heme-containing peptides clearly contained a single c-heme with optical properties indistinguishable from the tryptic heme-containing peptide from horse heart cytochrome c. No noncovalently bound heme was observed. One of the seven heme-containing peptides (T7) was unusual in that it released 2 amino acid residues after each cycle of the Edman degradation due to a nondisulfide cross-link and exhibited a Soret band that was broadened in both the ferric form at neutral pH and the pyridine ferrohemochrome. Subdigestion of peptide T7 with nonspecific proteases (Pronase, bromelain, or pepsin) resulted in the isolation of two smaller heme-containing peptides of unique sequences. One of these was spectrally identical to the other c-heme containing peptides, whereas the second was still apparently cross-linked, again releasing 2 amino acid residues after each Edman cycle. This second peptide possessed a heme-like chromophore with absorption bands (Soret, alpha and beta) red-shifted about 6 nm relative to the spectrum of c-heme-containing peptides. Thus, hydroxylamine oxidoreductase contains a total of eight covalently bound hemes per subunit, seven of which are c-hemes. The eighth, which is attached to a cross-linked peptide, is probably the unusual P460 heme which is unique to hydroxylamine oxidoreductase and thought to be at the active site.

Amino Acid Sequence↗
PubMed1991

Study of reactions induced by hydroxylamine treatment of esters of organic acids and of 3-ketoacids: application to the study of urines from patients under valproate therapy.

Hydroxylamine used at alkaline pH as oximating agent in the search for organic aciduria by gas chromatography/mass spectrometry (GC/MS) induces other chemical reactions. Esters are partially transformed in their corresponding hydroxamic acids. GC/MS characteristics of the trimethylsilylated derivatives of the hydroxamic acids arising from alpha-unsaturated esters are here reported. Their mass spectral fragmentation helps in the recognition of peaks arising from the glucuronides of 2-ene- and probably 2,3'-diene-valproic acid. By heating in the injection port of the gas chromatograph, part of some trimethylsilylated hydroxamic acids are transformed to the corresponding isocyanates by a Lossen-like rearrangement. In addition to the corresponding hydroxamic acids, hydroxylamine treatment of alpha-unsaturated esters forms 2-isoxazolidin-3-ones by intramolecular Michael addition. GC/MS characteristics of the trimethylsilylated derivatives of these compounds are reported. Submitted to hydroxylamine, 3-ketoacids forms 2-isoxazolin-5-ones by cyclization of the oximes after acidification. This explains the existence of two GC peaks observed from urine extracts of patients under valproate therapy, which correspond to two tautomers of 2-isoxazolin-5-one originating from the oximes of the 3-keto-valproic acid.

Gas Chromatography-Mass Spectrometry↗
PubMed1984

Effects of ligands and pH on the reactions of aspartate aminotransferase with aminooxyacetate and hydroxylamine.

The bimolecular association and first-order dissociation rate constants for the reactions of aminooxyacetate and hydroxylamine with the cytosolic aspartate aminotransferase (EC 2.6.1.1) of pig heart were estimated from pH 4.8 to pH 9.5. The acidic form of the enzyme (pK = 6.3) was more reactive than the unprotonated enzyme, but the rates of breakdown of the complexes were not affected by pH. The equilibrium dissociation constants, which were of the order of magnitude of 10(-7) M, were thus lowest at acidic pH values. Aminooxyacetate and hydroxylamine reacted similarly, with the former being more reactive. Glutarate and acetate inhibited the rates of formation and dissociation but had no effect on the overall equilibrium constants between enzyme and inhibitor. On the other hand, the substrate analog erythro-beta-hydroxy-L-aspartate, which forms a complex with the enzyme prosthetic group, acted competitively by preventing the inhibitors from reacting. The rate constants for formation of complexes with free pyridoxal phosphate were much less than those for the enzyme and, unlike the enzyme, hydroxylamine was more reactive than aminooxyacetate.

Acetates↗
PubMed1983

Interplay between hydroxylamine, metarhodopsin II and GTP-binding protein in bovine photoreceptor membranes.

The decay reactions of metarhodopsin II and the dissociation of the complex between rhodopsin (in the metarhodopsin II state) and the GTP-binding protein (G-protein) (in its inactive, GDP-binding form) have been compared at various concentrations of hydroxylamine. The reactions of the chromophore were measured by absorption changes in the visible range, the complex dissociation by changes in the near-infrared scattering. An additional monitor of the complex was given by the G-protein-dependent equilibrium between metarhodopsin I and metarhodopsin II. For all measurements, fragments of isolated bovine rod outer segments in suspension were used. In the absence of hydroxylamine, the rhodopsin-G-protein complex dissociated within 20-30 min at room temperature. The presence of hydroxylamine greatly accelerated (e.g., 5-fold at 1 mM NH2OH) the dissociation. Under all conditions, the free, dissociated G-protein can reassociate to metarhodopsin II produced by subsequent bleaching. Dissociation of the metarhodopsin II-G-protein complex required the decay of photoproducts with a maximal absorbance of 380 nm, but was not affected by the simultaneous presence of metarhodopsin III or metarhodopsin III - like photoproducts with a maximal absorbance between 450 and 470 nm. Despite the acceleration of metarhodopsin II-G-protein dissociation by NH2OH, metarhodopsin II-G-protein was relatively stabilized as compared to free metarhodopsin II. The ratio of the decay rates of free metarhodopsin II and metarhodopsin III-G-protein was increased as much as 10-fold in the presence of 25 mM NH2OH. The results indicate a mutual interdependence of retinal, opsin and G-protein.

Animals↗
PubMed1989

Detection of free radicals as intermediates in the methemoglobin formation from oxyhemoglobin induced by hydroxylamine.

Four distinct paramagnetic intermediates could be observed in the reaction between oxyhemoglobin and hydroxylamine using ESR spectroscopy. The radical species exhibited different stability properties thus different techniques were required for their detection. Two of them were identified as the hydronitroxide radical (NH2O.) and the hemoglobin-nitric oxide complex (Hb2+-NO). The third one is a low-spin iron-(III)-complex, possibly the methemoglobin-hydroxylamine adduct. A fourth paramagnetic species was detected only in the absence of the iron chelator DETAPAC thus indicating that free iron ions were responsible for the formation of this intermediate. The same species was observed when a Fenton system was used to generate the radicals. This species was identified as being the Fe(NO)2X2 complex described in the literature (X = inorganic anions such as OH- or PO3-(4). The identification of the radical intermediates detected in the hydroxylamine-induced methemoglobin formation contributes to a more detailed understanding of the reaction sequence.

Animals↗