Hydrazine, methylhydrazine and methylhydrazine sulfate carcinogenesis in Swiss mice. Failure of ammonium hydroxide to interfere in the development of tumors.
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Animals↗
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Enhanced biodegradation of methylhydrazine and hydrazine contaminated NASA wastewater in fixed-film bioreactor.
The aerobic biodegradation of National Aeronautics and Space Administration (NASA) wastewater that contains mixtures of highly concentrated methylhydrazine/hydrazine, citric acid and their reaction product was studied on a laboratory-scale fixed film trickle-bed reactor. The degrading organisms, Achromobacter sp., Rhodococcus B30 and Rhodococcus J10, were immobilized on coarse sand grains used as support-media in the columns. Under continuous flow operation, Rhodococcus sp. degraded the methylhydrazine content of the wastewater from a concentration of 10 to 2.5 mg/mL within 12 days and the hydrazine from approximately 0.8 to 0.1 mg/mL in 7 days. The Achromobacter sp. was equally efficient in degrading the organics present in the wastewater, reducing the concentration of the methylhydrazine from 10 to approximately 5 mg/mL within 12 days and that of the hydrazine from approximately 0.8 to 0.2 mg/mL in 7 days. The pseudo first-order rate constants of 0.137 day(-1) and 0.232 day(-1) were obtained for the removal of methylhydrazine and hydrazine, respectively, in wastewater in the reactor column. In the batch cultures, rate constants for the degradation were 0.046 and 0.079 day(-1) for methylhydrazine and hydrazine respectively. These results demonstrate that the continuous flow bioreactor afford greater degradation efficiencies than those obtained when the wastewater was incubated with the microbes in growth-limited batch experiments. They also show that wastewater containing hydrazine is more amenable to microbial degradation than one that is predominant in methylhydrazine, in spite of the longer lag period observed for hydrazine containing wastewater. The influence of substrate concentration and recycle rate on the degradation efficiency is reported. The major advantages of the trickle-bed reactor over the batch system include very high substrate volumetric rate of turnover, higher rates of degradation and tolerance of the 100% concentrated NASA wastewater. The results of the present laboratory scale study will be of great importance in the design and operation of an industrial immobilized biofilm reactor for the treatment of methylhydrazine and hydrazine contaminated NASA wastewater.
Alcaligenes↗
Mechanism of site-specific DNA damage induced by methylhydrazines in the presence of copper(II) or manganese(III).
DNA damage induced by methylhydrazines (monomethylhydrazine, 1,1-dimethylhydrazine, and 1,2-dimethylhydrazine) in the presence of metal ions was investigated by a DNA sequencing technique. 1,2-Dimethylhydrazine plus Mn(III) caused DNA cleavage at every nucleotide without marked site specificity. ESR-spin-trapping experiments showed that the hydroxyl free radical (.OH) is generated during the Mn(III)-catalyzed autoxidation of 1,2-dimethylhydrazine. DNA damage and .OH generation were inhibited by .OH scavengers and superoxide dismutase, but not by catalase. The results suggest that 1,2-dimethylhydrazine plus Mn(III) generates .OH, not via H2O2, and that .OH causes DNA damage. In the presence of Cu(II), DNA cleavage was caused by the three methylhydrazines frequently at thymine residues, especially of the GTC sequence. The order of Cu(II)-mediated DNA damage (1,2-dimethylhydrazine greater than monomethylhydrazine approximately 1,1-dimethylhydrazine) was not correlated with the order of methyl free radical (.CH3) generation during Cu(II)-catalyzed autoxidation (monomethylhydrazine greater than 1,1-dimethylhydrazine much greater than 1,2-dimethylhydrazine). Catalase and bathocuproine, a Cu(I)-specific chelating agent, inhibited DNA damage while catalase did not inhibit the .CH3 generation. The order of DNA damage was correlated with the order of ratio of H2O2 production to O2 consumption observed during Cu(II)-catalyzed autoxidation of methylhydrazines. These results suggest that the Cu(I)-peroxide complex rather than the .CH3 plays a more important role in methylhydrazine plus Cu(II)-induced DNA damage.
Autoradiography↗
Batch culture biodegradation of methylhydrazine contaminated NASA wastewater.
The batch culture degradation of NASA wastewater containing mixtures of citric acid, methylhydrazine, and their reaction product was studied. The organic contaminants present in the NASA wastewater were degraded by Achromobacter sp., Rhodococcus B30 and Rhodococcus J10. While the Achromobacter sp. showed a preference for the degradation of the citric acid, the Rhodococcus species were most effective in reducing the methylhydrazine and the reaction product. Removals of more than 50% were observed for citric acid, methylhydrazine and the reaction product when the NASA wastewater was inoculated with the microbes in batch cultures. Simulation and chemical characterization of citric acid and hydrazine mixtures show that the interaction is partly of a chemical nature and leads to the formation of a conjugated UV/Visible absorbing compound. An 'azo' carbonyl derivative of the citric acid, consistent with the spectral data obtained from the investigation, has been proposed as the possible product.
Alcaligenes↗
The ex vivo effects of procarbazine and methylhydrazine on some rat amine oxidase activities.
Monoamine oxidase (MAO) and semicarbazide-sensitive amine oxidase (SSAO) activities were examined in homogenates of various rat tissues following i.p. administration of procarbazine or methylhydrazine. Both compounds inhibited SSAO in a dose-dependent manner in all tissues examined, with methylhydrazine the more potent agent in this respect. Little inhibition of MAO could be detected in most cases. However, hepatic MAO-B activity was potentiated significantly in rats receiving methylhydrazine and both drugs caused a dose-dependent potentiation of MAO-A in homogenates of brown adipose tissue. The potential use of these compounds in vivo as selective SSAO inhibitors is discussed.
Adipose Tissue, Brown↗
Oxidation of methylhydrazines to mutagenic methylating derivatives and inducers of the adaptive response of Escherichia coli to alkylation damage.
The methylhydrazines, monomethylhydrazine, 1,1-dimethylhydrazine, and 1,2-dimethylhydrazine, are known carcinogens but only weak mutagens in the Ames test. Chemical oxidation of these compounds by potassium ferricyanide greatly enhanced their mutagenicity to an Escherichia coli ada mutant and converted them into inducers of the adaptive response of E. coli to alkylation damage. Enzymatic oxidation of monomethylhydrazine by horseradish peroxidase-H2O2 also yielded products which induced the adaptive response. Thus, methylhydrazines can be oxidized to active DNA-methylating derivatives which generate methylphosphotriesters (the inducing signal of the adaptive response), O6-methylguanine and/or O4-methylthymine (the miscoding bases repaired by the Ada protein) in DNA. These observations support the suggestion that metabolic oxidation of methylhydrazines in mammalian systems may be required to generate the mutagenic/carcinogenic derivatives.
1,2-Dimethylhydrazine↗
Synthesis and evaluation of 1-(arylsulfonyl)-2-[(methoxycarbonyl)sulfenyl]-1-methylhydrazines++ + as antineoplastic agents.
1-(Arylsulfonyl)-2-[(methoxycarbonyl)sulfenyl]-1-methylhydrazines, with the potential to function as biological methylating agents, were synthesized and evaluated as antineoplastic agents against the L1210 leukemia and the B16 melanoma in mice. All of the compounds of this class had significant activity against the B16 melanoma, with the most active compound, 2-[(methoxycarbonyl)sulfenyl]-1-methyl-1-[(4- methylphenyl)sulfonyl]hydrazine, producing percent T/C values for B16 melanoma tumor bearing mice of between 182 and 232 at dosage levels of from 12.5 to 50 mg/kg daily for 6 consecutive days. In contrast to the related class of agents, the N,N'-bis(sulfonyl)hydrazines reported earlier by this laboratory,1 the 1-(arylsulfonyl)-2-[(methoxycarbonyl)sulfenyl]-1-methylhydrazines were found to be inactive against the L1210 leukemia in vivo.
Animals↗
Detection of hydrazine, methylhydrazine and isoniazid by capillary electrophoresis with a 4-pyridyl hydroquinone self-assembled microdisk platinum electrode.
Capillary electrophoresis (CE)/electrochemical detection (EC) for the simultaneous detection of hydrazine, methylhydrazine, and isoniazid has been developed with a 4-pyridyl hydroquinone self-assembled microdisk platinum electrode. Such an electrode has very high catalytic ability for hydrazines and they could be detected even at 0.0 V. The responses for hydrazine, methylhydrazine, and isoniazid are linear over 3 orders of detected concentration and of magnitude of 0.2-400 microM, 0.2-400 microM, 0.5 microM-2 mM, with correlation coefficients of 0.9998, 0.9991, and 0.9982, respectively. And they could be detected to levels of 0.1, 0.1 and 0.2 microM, respectively. This modified electrode was found to be very stable and reproducible when continuously used as detector for capillary electrophoresis for period of at least 4 weeks with no apparent loss of response.
Electrochemistry↗
Morphological and biochemical effects of 1,2-dimethylhydrazine and 1-methylhydrazine in rats and mice.
Single toxic doses of 1,2-dimethylhydrazine induced mild centrilobular necrosis of the liver in rats and mice. Ultrastructural studies showed hepatic nuclear changes including nucleolar microsegregation and changes in the endoplasmic reticulum and mitochondria. 1-Methylhydrazine caused little morphological change in the liver. Tumours of the colon and kidney and also massive cystic hyperplasia of the liver were found in some of the rats and tumours of the anal margin and kidney in some of the mice, following single doses of 1,2-dimethylhydrazine. Incorporation of amino acids into rat liver proteins was inhibited by 1,2-dimethylhydrazine, which also caused disaggregation of hepatic polysomes. No effects on hepatic protein synthesis by 1,1-dimethylhydrazine or 1-methylhydrazine were observed. Similarities between the effects of 1,2-dimethylhydrazine, cycasin and dimethylnitrosamine are discussed.
Animals↗
Formation of methylhydrazine from acetaldehyde N-methyl-N-formylhydrazone, a component of Gyromitra esculenta.
Gyromitrin, acetaldehyde N-methyl-N-formylhydrazone, is a toxin present in edible wild mushroom Gyromitra esculenta. At 37 degrees under different acidic conditions (pH 1 to 3), mimicking the milieu of human stomach, gyromitrin is converted to methylhydrazine, a known tumor inducer in mice and hamsters, through an intermediate, N-methyl-N-formylhydrazine. In addition, methylhydrazine is formed in the mouse stomach after p.o. administration of gyromitrin. These findings imply that consumption of G. esculenta could present a carcinogenic, as well as an acutely toxic, health hazard.
Animals↗
The effects of the methylating agent 1,2-bis(methylsulfonyl)-1-methylhydrazine on morphology, DNA content and mitochondrial function of Trypanosoma brucei subspecies.
Repeated exposure of trypanosomes in vitro or in vivo to low concentrations of the methylating agent 1,2-bis(methylsulfonyl)-1-methylhydrazine induces a series of moderately synchronous morphological and biochemical changes. Cell division halts and the long-slender bloodstream forms transform to short-stumpy forms via larger intermediate-stage cells which contain approximately double the normal G2 content of DNA. In common with naturally occurring short-stumpy trypanosomes, drug-induced short-stumpy forms do not infect rodents and when transferred to Cunningham's medium, transform to and replicate as procyclics. Furthermore, these short-stumpy forms exhibit alpha-ketoglutarate supported motility and oxygen consumption, acquire the ability to reduce nitroblue tetrazolium (NADH diaphorase positivity) and appear to be in the G1 or G0 stage of the cell cycle based upon DNA content.
Animals↗
Metabolism and activation of 1,1-dimethylhydrazine and methylhydrazine, two products of nitrosodimethylamine reductive biotransformation, in rats.
Nitrosodimethylamine (DMN) and two of its metabolites, methylhydrazine (MH) and 1,1-dimethylhydrazine (UDMH), were metabolized to CO2 by liver slices obtained from Sprague-Dawley rats. Under the conditions used, DMN and MH produced reactive metabolites that bound covalently to nucleic acids, but UDMH did not. Rat liver microsomes or 9,000 X g supernatants were able to transform DMN, MH, and UDMH to CH2O. In the cases of MH and UDMH, enzymatic and nonenzymatic pathways of CH2O formation were observed in both liver microsomes and 9,000 X g supernatants. DMN, MH, and UDMH led to covalent binding (CB) to proteins in incubation mixtures containing either microsomes or 9,000 X g supernatants. In the case of DMN, the process was enzymatic and required NADPH in both cellular fractions. In the case of MH, the process was enzymatic in microsomes and required NADPH and O2. With UDMH or MH and 9,000 X g supernatants, nonenzymatic interactions resulting in CB to proteins dominated. All these results suggest that part of the CO2 produced during DMN metabolism might be derived from UDMH and MH. Similarly, a significant part of the CB of DMN metabolites to proteins in incubation mixtures containing microsomes or 9,000 X g supernatants might be derived from enzymatic and nonenzymatic reactions of UDMH or MH. Also, a minor part of the CB of DMN-reactive metabolites to nucleic acids might have resulted from MH's further biotransformation to reactive metabolites. Overall, biotransformation of DMN and MH might not be a detoxication process, as previously thought, but one related to some of the DMN toxic effects.
Animals↗
Evaluation of 2-(methylaminosulfonyl)-1-(arylsulfonyl)-1-methylhydrazines as anticancer agents.
Seven new 2-(methylaminosulfonyl)-1-(arylsulfonyl)-1-methylhydrazines were prepared. The anticancer activity of these compounds was assessed in murine Ehrlich ascites carcinoma (EAC) by in vivo screening. Moderate in vivo activity in EAC was exhibited by three compounds. All of them were screened in vitro against a battery of human tumor cell lines at the National Cancer Institute (NCI), USA. One of them, compound 3a has displayed highly significant specificity in the renal tumor cell line RXF 393. These three compounds were also assessed for in vitro anti-HIV activity at the NCI, however, they have not reached the criteria of significant activity. The alkylating activity of the compounds was determined by measuring the absorbance of the alkylated product of 4-(4-nitrobenzyl)pyridine. It has been found that they are capable of acting as chemical alkylating agents.
Animals↗
The electron impact, chemical ionization and fast atom bombardment positive ion mass spectra of 1,2-bis(sulfonyl)methylhydrazines.
A series of bis(sulfonyl)-1-methylhydrazines were analyzed by positive ion electron impact (EI), chemical ionization (CI) and fast atom bombardment (FAB) mass spectrometry. Since these compounds showed activity against the L1210 leukemia, an understanding of their mass spectral behavior is important should the structural characterization of metabolites be required. FAB proved to be the most useful technique, generally providing abundant protonated molecule ion peaks, in contrast to the weak peaks observed with CI (ammonia or isobutane) and the total absence of molecular ion peaks in the EI mass spectra. In addition, utilizing FAB eliminated the problem of thermal decomposition, which was very difficult to control under EI and CI experimental conditions. Fragments observed in FAB and CI mass spectra were consistent with protonation at the methyl-bearing nitrogen. One can locate the R1 and R2 moieties relative to the methyl-bearing nitrogen in FAB and CI by assigning that nitrogen as the site of protonation, with subsequent elimination of R2SO2H.
Antineoplastic Agents↗
Active-site structure of the soluble quinoprotein glucose dehydrogenase complexed with methylhydrazine: a covalent cofactor-inhibitor complex.
Soluble glucose dehydrogenase (s-GDH) from the bacterium Acinetobacter calcoaceticus is a classical quinoprotein. It requires the cofactor pyrroloquinoline quinone (PQQ) to catalyze the oxidation of glucose to gluconolactone. The precise catalytic role of PQQ in s-GDH and several other PQQ-dependent enzymes has remained controversial because of the absence of comprehensive structural data. We have determined the crystal structure of a ternary complex of s-GDH with PQQ and methylhydrazine, a competitive inhibitor of the enzyme. This complex, refined at 1.5-A resolution to an R factor of 16.7%, affords a detailed view of a cofactor-binding site of s-GDH. Moreover, it presents the first direct observation of covalent PQQ adduct in the active-site of a PQQ-dependent enzyme, thereby confirming previous evidence that the C5 carbonyl group of the cofactor is the most reactive moiety of PQQ.
Binding Sites↗
Formation of 8-methylguanine as a result of DNA alkylation by methyl radicals generated during horseradish peroxidase-catalyzed oxidation of methylhydrazine.
Methylhydrazine oxidation promoted by horseradish peroxidase-H2O2 or ferricyanide led to the generation of high yields of methyl radicals and to the formation of 7-methylguanine and 8-methylguanine upon interaction with calf thymus DNA. Methyl radicals were identified by spin-trapping experiments with alpha-(4-pyridyl-1-oxide)-N-tert-butyl nitrone and tert-nitrosobutane. The methylated guanine products were identified in the neutral hydrolysates of treated DNA by high pressure liquid chromatography (HPLC) analysis and spiking with authentic samples. The structure of 8-methylguanine, a product not previously reported in enzymatic systems, was confirmed by HPLC chromatography, UV absorbance, and mass spectrometry. The formation of 8-methylguanine suggests a possible role for carbon-centered radicals as DNA-alkylating agents.
Alkylation↗
Hydrazine and methylhydrazine as recA+-independent mutagens in Escherchia coli.
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DNA Ligases↗
Simultaneous determination of hydrazine, methylhydrazine, and 1,1-dimethylhydrazine in air by derivatization/gas chromatography.
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1,2-Dimethylhydrazine↗