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PubMed1980

The neuronal and extraneuronal uptake and deamination of 3H-(-)-phenylephrine in the perfused rat heart.

The neuronal and extraneuronal uptake and deamination of 3H-(-)-phenylephrine was studied in perfused rat hearts obtained from reserpine-pretreated animals. 1. Under the conditions of steady-state perfusion with 5 mumol/l 3H-(-)-phenylephrine slightly more than 50% of total deamination took place in adrenergic nerve endings, slightly less than 50% in the extraneuronal tissue. 2. 3H-(-)-phenylephrine is preferentially deaminated to the glycol metabolite. 3. There is pronounced non-saturable, cocaine- and corticosterone-resistant uptake of 3H-(-)-phenylephrine in the perfused rat heart. 4. The apparent rate constants for the efflux of the glycol metabolite is about 20 times higher than that for the efflux of the acid metabolite. 5. For both the glycol and the acid metabolite of 3H-(-)-phenylephrine, apparent rate constants for the efflux declined when the duration of the perfusion with the labelled parent amine was prolonged. This phenomenon was also observed when the deamination of 3H-(-)-phenylephrine was restricted to either the adrenergic nerve endings or the extraneuronal tissue. These results are interpreted as evidence for a distribution of each metabolite into at least two kinetically different compartments. 6. This was confirmed for the acid metabolite by determination of a biphasic efflux curve in wash-out experiments in which MAO was inhibited during wash-out (after an initial loading of the adrenergic nerve endings with 3H-(-)-phenylephrine).

Animals↗
PubMed1992

Phenotypic analysis of 1-B-D-arabinofuranosylcytosine deamination in patients treated with high doses and correlation with response.

Two phenotypes for 1-B-D-arabinofuranosylcytosine (ara-C) deamination corresponding to a ratio of distribution for "slow" (ratio, less than or equal to 14) vs "fast" (ratio, greater than 14) deaminators of 70%:30%, have been determined on the basis of studies on plasma ratios of 1-B-D-arabinofuranosyluracil/ara-C (ara-U/ara-C) in 56 subjects treated with high-dose ara-C (3 g/m2 infused i.v. over 3 h). A positive correlation of age with the concentration of ara-U was observed. In a subgroup of 36 patients with leukemia, the ara-U/ara-C pattern was similar to that observed for all 56 subjects. In these leukemic patients, who were treated with combinations of ara-C plus other conventional agents, a tendency toward a positive response (complete response + partial response) was found for those showing low ara-U/ara-C ratios (slow deaminators). The phenotypic effect of deamination in acute leukemia needs to be evaluated prospectively.

Adolescent↗
PubMed1989

A rabbit liver constitutive form of cytochrome P450 responsible for amphetamine deamination.

A cytochrome P450 isozyme responsible for amphetamine deamination was purified from hepatic microsomes of untreated rabbits. The purification procedures consisted of a set of column chromatographies with omega-aminooctyl-Sepharose 4B, DEAE-cellulose, CM-Sephadex C-50, and hydroxyapatite. The deamination activity was determined by measuring the formation of phenylacetone after derivatization to the p-nitrobenzyloxim by HPLC. This isozyme, which was designated P450APD, showed a monomeric molecular weight of 51,000 in sodium dodecyl sulfate-polyacrylamide gel electrophoresis and exhibited an absorption maximum of reduced CO complex at 451 nm. On the basis of the specificity toward testosterone metabolism and the N-terminal amino acid sequence, P450APD was attributed to a member of P450 class IIC subfamily, which is identical or closely related to LM3b (D. R. Koop and M. J. Coon (1979) Biochem, Biophys, Res. Commun. 91, 1075-1081), form 3b (E. F. Johnson (1980) J. Biol. Chem. 255, 304-309), and other similar preparations. Antibody against the P450APD inhibited about 80% of the amphetamine deamination activity in rabbit hepatic microsomes as well as in the reconstitution system of this P450. The present results support that P450APD is the major P450 isozyme responsible for amphetamine deamination in rabbit liver.

Amphetamine↗
PubMed1993

Echinomycin, a bis-intercalating agent, induces C-->T mutations via cytosine deamination.

Echinomycin, a bis-intercalating, antitumor drug, has been studied for its ability to induce the deamination of cytosine to uracil (C-->U) in double-stranded DNA. We have employed a sensitive lacZ alpha-complementation reversion assay to detect G.C-->A.T mutations at a number of sites in M13mp2 DNA to determine the extent to which distortions of DNA structure induced by echinomycin may affect C-->U rates. When double-stranded M13mp2 DNA with a 12-base target containing a CpG site was incubated at 37 degrees C, the reversion frequency of the echinomycin-treated DNA increased linearly over time, with a rate constant 3-fold greater than DNA incubated without echinomycin. Of the 11 ways that blue pseudo-revertants can occur in the target, 96% of the observed revertants arose from C-->T and tandem CC-->TT transitions, with 78% attributable to single-base C-->T changes at three sites. Transfection into ung+ cells decreased the reversion frequencies by 85% to near background levels, indicating that the increase in C-->T mutations was due to deamination of C to U. The cytosine deamination rate constants for the entire target at pH 6.0 and 37 degrees C were 1.2 x 10(-11) sec-1 for untreated DNA and 3.5 x 10(-11) sec-1 for echinomycin-treated DNA. The increase in C-->T mutation rates occurred at cytosines both proximal and distal to a CpG echinomycin-binding site. We hypothesize that this increase in deamination rate is due to a more open or single-stranded DNA structure caused by the echinomycin: DNA interaction.

Base Sequence↗
PubMed1982

Heat- and alkali-induced deamination of 5-methylcytosine and cytosine residues in DNA.

5-methylcytosine residues in DNA underwent deamination at high temperatures. Furthermore, their rate of deamination at neutral or alkaline pH was greater than that of cytosine residues in DNA. As sources of [14C]-5-methylcytosine-containing DNA, we used bacteriophage XP-12 DNA, in which 5-methylcytosine residues completely replace C residues, and calf thymus DNA experimentally substituted with [14C] 5-methylcytosine residues. Upon incubation at 95 degrees C in a physiological buffer or at 60 degrees C in 1 M NaOH, the respective rates of deamination of 5-methylcytosine residues were about 3- and 1.5-times those on cytosine residues. Under the same conditions, the free 5-methyldeoxycytidine was converted to thymidine more rapidly than deoxycytidine was converted to deoxyuridine. The reactions at physiological pH and elevated temperature suggest that deamination of 5-methylcytosine residues may yield a significant portion of spontaneous mutations in vivo, especially in view of the lack of thymine-specific mismatch repair systems with specificity and efficiency comparable to that of uracil excision repair systems.

5-Methylcytosine↗
PubMed2006

Identification of monoamine oxidase and cytochrome P450 isoenzymes involved in the deamination of phenethylamine-derived designer drugs (2C-series).

In recent years, several compounds of the phenethylamine-type (2C-series) have entered the illicit drug market as designer drugs. In former studies, the qualitative metabolism of frequently abused 2Cs (2C-B, 2C-I, 2C-D, 2C-E, 2C-T-2, 2C-T-7) was studied using a rat model. Major phase I metabolic steps were deamination and O-demethylation. Deamination to the corresponding aldehyde was the reaction, which was observed for all studied compounds. Such reactions could in principal be catalyzed by two enzyme systems: monoamine oxidase (MAO) and cytochrome P450 (CYP). The aim of this study was to determine the human MAO and CYP isoenzymes involved in this major metabolic step and to measure the Michaelis-Menten kinetics of the deamination reactions. For these studies, cDNA-expressed CYPs and MAOs were used. The formation of the aldehyde metabolite was measured using GC-MS after extraction. For all compounds studied, MAO-A and MAO-B were the major enzymes involved in the deamination. For 2C-D, 2C-E, 2C-T-2 and 2C-T-7, CYP2D6 was also involved, but only to a very small extent. Because of the isoenzymes involved, the 2Cs are likely to be susceptible for drug-drug interactions with MAO inhibitors.

Cytochrome P-450 Enzyme System↗
PubMed1996

The effect of deamination and/or blocking arginine residues on the molecular assembly of acid-extracted rat tail tendon collagen.

We describe the effect of deamination of lysine and blocking of arginine residues on the assembly of collagen into native fibrils and SLS aggregates. Treatment of collagen solutions with one or both of these procedures does not prevent the formation of fibrils or SLS aggregates but reduces their ability to form assemblies with accurate longitudinal registration. These observations provide direct confirmation that hydrophobic interactions are important in collagen assembly. Unbanded fibrils were formed within the first 24 h at 4 degrees C from both acidic and neutralized deaminated and from neutralized control collagen solutions, transversely banded fibrils appearing later. This is compatible with the suggestion that initially, collagen fibrils are assembled by lyotropic liquid crystallization and with other observations which suggest that collagen molecules are initially free to move laterally within the fibril before being locked into place. Fibrils assembled from deaminated collagen solution show two variant longitudinal registration patterns which grade into one another. This suggests that, with a reduction in positively charged side chains, the thermodynamic energy minima responsible for longitudinal registration are less sharp compared with control collagen solutions. Reduction of positive charge by chemical modification helps to explain why the chemical modifications reduce swelling of collagen fibres. It also helps to explain why fibrils form spontaneously at 4 degrees C in both arginine-blocked and deaminated collagen solutions. Thus chemical modifications of rat tail tendon provides new insight into the mechanisms in collagen assembly.

Acetates↗
PubMed2003

Oxidative deamination of benzylamine by glycoxidation.

In the present study, model reactions for the oxidative deamination by glycoxidation using benzylamine were undertaken to elucidate the detail of the reaction. Glucose, 3-deoxyglucosone (3-DG), and methylglyoxal (MG) oxidatively deaminated benzylamine to benzaldehyde in the presence of Cu(2+) at a physiological pH and temperature but not glyoxal. 3-DG and MG were more effective oxidants than glucose. We have determined the effects of metal ions, pH, oxygen, and radical scavengers on the oxidative deamination. The formation of benzaldehyde was greatest with Cu(2+), and was accelerated at a higher pH and in the presence of oxygen. EDTA, catalase, and dimethyl sulfoxide significantly inhibited the oxidation, suggesting the participation of reactive oxygen species. From these results, we propose a mechanism for the oxidative deamination by the Strecker-type reaction and the reactive oxygen species-mediated oxidation during glycoxidation.

Benzaldehydes↗
PubMedDate not supplied

Deamination of single-stranded DNA cytosine residues in aerobic nitric oxide solution at micromolar total NO exposures.

Deamination of cytosine to uracil is a potential source of mutations in DNA. Here we examine the deaminating ability of aerobic nitric oxide (NO) toward single-stranded DNA at very low (micromolar and below) total exposures, using a sensitive genetic method that allows us to study a single deamination event at a specific site in a 7200-nucleotide DNA molecule within a pool of ca. 100,000 other identical DNA molecules. We incubated gapped C141 M13mp2 DNA with the NO-generating compound, Et2N[N(O)NO]Na (DEA/NO), in aerobic buffer for 16 h to ensure complete autoxidation at pH 7.4 and 37 degrees C. After ultrafiltration to remove small molecules, the DNA was transformed into isogenic Escherichia coli cultures that were either deficient (NR9404, ung-) or proficient (MC1061, ung+) in uracil-DNA glycosylase activity. The gapped DNA was constructed such that the target (CCC) codon was contained in a short single-stranded segment of otherwise double-stranded circular DNA, and the incubation was performed in a closed system to prevent loss of NO to the atmosphere before the reaction was complete. An increase in the reversion frequency in the ung- strain was noted between 0 and 1 microM DEA/NO, and the reversion frequency leveled out between 3 and 30 microM. However, 30 microM "spent" DEA/NO (i.e., that which was similarly incubated for 4 h to complete the autoxidation of NO before the DNA was added) did not increase reversion frequency relative to control. Nearly all (42/43) of the mutations identified after 1 microM DEA/NO treatment were C-->T transitions, and reversion frequency in the isogenic ung+ strain was lower than in the ung- strain. The data are consistent with the hypothesis that total NO exposures in the mumol/L range can lead to C-->T mutations via a mechanism most probably involving deamination of DNA cytosine residues.

Aerobiosis↗
PubMed1998

Inhibition of nitrous acid-dependent tyrosine nitration and DNA base deamination by flavonoids and other phenolic compounds.

Exposure of tyrosine or DNA bases to acidic nitrite at low pH results in the nitration of tyrosine and the formation of base deamination products, respectively. At pH 1, hypoxanthine and xanthine are formed from the deamination of adenine and guanine, respectively, whereas under the same conditions, uracil is not detected. The yield of 3-nitrotyrosine derived from interaction of equimolar nitrite and tyrosine at pH 1 is approximately 50% of that obtained from equimolar peroxynitrite-tyrosine interactions at pH 7. 4. The ability of a range of plant phenolic constituents to prevent damage mediated by acidic nitrite was also examined in comparison with the activity of vitamin C. The epicatechin/gallate family of flavonols, constituents of green tea, red wine, etc., demonstrates the most extensive inhibitory properties against both tyrosine nitration and base deamination. The results also show that ascorbic acid is a poor inhibitor of nitration or deamination under acidic conditions such as those of the stomach. The ability of plant phenolics to scavenge reactive nitrogen species derived from acidic nitrite may contribute to the protective effects of tea polyphenols against gastric cancer.

Chromatography, High Pressure Liquid↗
PubMed1998

Identification of a nickel(II) binding site on hemoglobin which confers susceptibility to oxidative deamination and intramolecular cross-linking.

Complexation of Ni(II) with native state recombinant hemoglobin is shown to produce NH2-terminal deamination and globin cross-linking in the presence of the oxidant potassium peroxymonosulfate (OxoneTM). Both the oxidative deamination and cross-linking are exclusive to the beta chains. Recombinant hemoglobin mutants have been created to identify protein sequence requirements for these reactions. It was found that His-2 of the beta globin is required for redox active Ni(II) complexation, oxidative deamination, and cross-linking. The oxidative deamination results in the formation of a free carbonyl in place of the NH2-terminal amine of the beta chain. Most cross-linking of the beta globin occurs intramolecularly, forming beta globin dimers. Structural characterization of the beta globin dimers indicates the presence of heterogeneous cross-links within the central hemoglobin cavity between the NH2 terminus of one beta chain and the COOH-terminal region of the other.

Amino Acid Sequence↗
PubMed1999

Nickel-catalyzed N-terminal oxidative deamination in peptides containing histidine at position 2 coupled with sulfite oxidation.

Peptides containing histidine at position 2 were observed to undergo spontaneous N-terminal oxidative deamination in aqueous solution in the presence of Ni(II), sulfite, and ambient oxygen. The reaction resulted in the formation of a free carbonyl on the N-terminal alpha-carbon (alpha-ketoamide) and was catalytic with respect to nickel. This oxidative deamination was confirmed by 13C NMR, 1H NMR, mass spectrometry, and chemical tests. No evidence of modification of histidine was found. It was demonstrated that the nickel-dependent N-terminal oxidative deamination also occurred in His-2 peptides using potassium peroxymonosulfate (oxone) as an oxidant. When oxone was used, oxygen was not required for the deamination to proceed. The results suggest that both nickel-catalyzed reactions (sulfite and oxygen, and oxone) produce an imine intermediate that spontaneously hydrolyzes to form the free carbonyl. These findings may provide a physiologically relevant model for oxidative carbonyl formation in vivo, as well as a useful method for producing a site-specific carbonyl on peptides and proteins.

Chromatography, High Pressure Liquid↗
PubMed1996

Methylation inhibitors can increase the rate of cytosine deamination by (cytosine-5)-DNA methyltransferase.

The target cytosines of (cytosine-5)-DNA methyltransferases in prokaryotic and eukaryotic DNA show increased rates of C-->T transition mutations compared to non-target cytosines. These mutations are induced either by the spontaneous deamination of 5-mC-->T generating inefficiently repaired G:T rather than G:U mismatches, or by the enzyme-induced C-->U deamination which occurs under conditions of reduced levels of S-adenosylmethionine (AdoMet) and S-adenosylhomocysteine (AdoHcy). We tested whether various inhibitors of (cytosine-5)-DNA methyltransferases analogous to AdoMet and AdoHcy would affect the rate of enzyme-induced deamination of the target cytosine by M.HpaII and M.SssI. Interestingly, we found two compounds, sinefungin and 5'-amino-5'-deoxyadenosine, that increased the rate of deamination 10(3)-fold in the presence and 10(4)-fold in the absence of AdoMet and AdoHcy. We have therefore identified the first mutagenic compounds specific for the target sites of (cytosine-5)-DNA methyltransferases. A number of analogs of AdoMet and AdoHcy have been considered as possible antiviral, anticancer, antifungal and antiparasitic agents. Our findings show that chemotherapeutic agents with affinities to the cofactor binding pocket of (cytosine-5)-DNA methyltransferase should be tested for their potential mutagenic effects.

Bacteria↗
PubMed1993

Oxidative deamination of methylamine by semicarbazide-sensitive amine oxidase leads to cytotoxic damage in endothelial cells. Possible consequences for diabetes.

Methylamine was observed to be deaminated by several semicarbazide-sensitive amine oxidases, which were prepared from blood and vascular tissues of various species, including humans. Although methylamine itself is relatively nontoxic toward endothelial cells obtained from both human umbilical vein and calf pulmonary artery, it becomes very toxic in the presence of SSAO. SSAO inhibitors (i.e., MDL-72974A) effectively protected the cells from methylamine-SSAO-induced damage. The cytotoxicity seems, therefore, to be a consequence of the deamination of methylamine. Our findings suggest that formaldehyde, the deaminated product of methylamine, may be responsible for these toxic effects. Human serum, which also contains SSAO, was also capable of deaminating methylamine and causing cytotoxicity to cultured endothelial cells. Both methylamine and SSAO circulate in human blood, and their concentrations in the blood of normal healthy subjects are quite close to those required to induce cytotoxicity in tissue-cultured cells. Both SSAO activity and methylamine levels have been reported to be increased in the blood of diabetic individuals. Blood SSAO activity also has been reported to be elevated in the blood of STZ-induced diabetic rats. It is possible, therefore, that an abnormal metabolism of methylamine may be involved in endothelial injury, and that it may subsequently induce atherosclerotic plaque formation and thus be involved in the cardiovascular disorders seen in diabetes.

Amine Oxidase (Copper-Containing)↗
PubMed1975

Deamination of amino acids in the small intestine of chickens fed meat meal.

The loss of amino acids by bacterial deamination in the small intestine of chicks fed heated and unheated meat meal was studied by incubating the intestinal contents in vitro. The loss of amino acids by bacterial deamination was found to take place mainly in the lower small intestine. Deamination of amino acids was significantly higher in the contents of the small intestine of chicks fed a meat meal compared to the freeze-dried raw materials, and this deamination was reduced by the addition of 50 p.p.m. penicillin to the meat meal.

Amino Acids↗
PubMed1992

[Deamination of adenosine monophosphate in the rat brain in hyperoxia, hypoxia, and cold stress].

The causes of the adenosine monophosphate (AMP) deamination increase in rat brain mitochondria under conditions of hyperoxia, hypoxia and cold stress were studied. Data from the inhibitory analysis suggest that the increased intensity of AMP deamination under hypoxia is conditioned by the alterations in the substrate specificity of type A monoamine oxidase which acquires the ability to deaminate AMP. The enhancement of AMP deamination under hyperoxia and cold stress is due to the activation of true AMP deaminase in the mitochondrial fraction. The cytoplasmic AMP deaminase activity remains unchanged thereby. The effects of the AMP deaminase specific effectors, ATP and inorganic phosphate, were investigated.

AMP Deaminase↗
PubMedDate not supplied

[The effect of psychotropic substances on the deamination of monoamines in the rat brain].

A comparative study of antimonoamine oxidase activity of psychotropic agents of different classes was made. Phenothiazine, butyrophenone and atypical neuroleptics were found to suppress deamination of 2-phenylethylamine in the brain. Tranquilizers of benzodiazepine structure appeared to be inactive with respect to monoamine oxidase (MAO) of the brain. Anticonvulsants (except difenin) weakly inhibit serotonin deamination and, on the contrary, difenin stimulates serotonin- and 2-phenylethylamine deamination. Antidepressants--MAO inhibitors--more actively reduce the rate of serotonin deamination, and tricyclic antidepressant desimipramine is similar to aminazine by its effect on MAO. Phenamine is a potent MAO inhibitor. The effect of cocaine is significantly less pronounced.

Animals↗
PubMed1987

Deamination rates of 1-beta-D-arabinofuranosylcytosine, deoxycytidine and 5-methyl-2'-deoxycytidine in seven hematopoietic cell lines.

Enzymatic deamination activity was determined with tritium-labelled substrates in seven established hematopoietic cell lines, in order to compare deamination rates in intact vs. broken cells with cytosine arabinoside, deoxycytidine and 5-methyldeoxycytidine. Deaminase activity was found in all the cell lines, although it was very low in mouse leukemia L1210 cells. The deamination activity of intact cells varied from 1.0 to 38.3 pmoles/micrograms protein/30 min, being highest in the human null-cell ALL line (NALL-1), the human promyelocytic leukaemia line (HL-60) and the human T-ALL line (JM). The variation in specific activities in the broken cells was between 0.9 and 30.2 pmoles/micrograms protein/30 min. The deamination rate of deoxycytidine was in general higher than that of 5-methyldeoxycytidine or cytosine arabinoside.

Animals↗