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Biochemical Pharmacology May 1993The neutrophil-catalyzed metabolism of hydrazine derivatives to carbon-centered radicals was investigated by the spin-trapping technique using... (Comparative Study)
Comparative Study
The neutrophil-catalyzed metabolism of hydrazine derivatives to carbon-centered radicals was investigated by the spin-trapping technique using alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone (POBN). Oxidation of methylhydrazine (MeH), dimethylhydrazine (DMH), phenylethylhydrazine or procarbazine by neutrophils from rat peritoneal exudates led to the formation of alkyl radicals. The monosubstituted hydrazine oxidation by phorbol ester (PMA)- or Zymocel-activated neutrophils generated, on average, 2- to 4-fold more POBN-alkyl adducts than di-substituted hydrazines. Supernatant from sonicated neutrophils generated similar yields of radicals. Azide, an inhibitor of myeloperoxidase, effectively reduced the neutrophil-catalyzed radical yield from the oxidation of MeH but not DMH. On the other hand, superoxide dismutase and catalase effectively inhibited radical formation in DMH metabolism by PMA-activated neutrophils, in contrast to MeH metabolism. Our results show that neutrophils are able to metabolize hydrazine derivatives, the pathway depending on the hydrazine substitution. Alkyl radical production during the oxidation of mono-substituted derivatives, such as MeH, was mediated mainly by myeloperoxidase, and that of di-substituted derivatives, such as DMH, was mediated mainly by active oxygen species.
Topics: 1,2-Dimethylhydrazine; Animals; Azides; Dimethylhydrazines; Female; Free Radicals; Hydrazines; L-Lactate Dehydrogenase; Monomethylhydrazine; Neutrophils; Nitrogen Oxides; Peritoneal Cavity; Peroxidase; Procarbazine; Pyridines; Rats; Rats, Wistar; Reactive Oxygen Species; Tetradecanoylphorbol Acetate
PubMed: 8388211
DOI: 10.1016/0006-2952(93)90451-2 -
Analytical Chemistry 1993Hydrazine (HZ) and monomethylhydrazine (MMH) in air were monitored continuously using a hand-held ion mobility spectrometer equipped with membrane inlet, 63Ni ion...
Hydrazine (HZ) and monomethylhydrazine (MMH) in air were monitored continuously using a hand-held ion mobility spectrometer equipped with membrane inlet, 63Ni ion source, acetone reagent gas, and ambient temperature drift tube. Response characteristics included detection limit, 6 ppb; linear range, 10-600 ppb; saturated response, >2 ppm; and stable response after 15-30 min. Ammonia interfered in hydrazines detection through a product ion with the same drift time as that for MMH and HZ. Acetone reagent gas was replaced with 5-nonanone to alter drift times of product ions and separate ammonia from MMH and HZ. Patterns in mobility spectra, ion identifications from mass spectra, and fragmentation cross-sections from collisional-induced dissociations suggest that drift times are governed by ion-cluster equilibria in the drift region of the mobility spectrometer. Practical aspects including calibration, stability, and reproducibility are reported from the use of a hand-held mobility spectrometer on the space shuttle Atlantis during mission STS-37.
Topics: Ammonia; Environmental Monitoring; Hydrazines; Ions; Ketones; Monomethylhydrazine; Space Flight
PubMed: 11537896
DOI: 10.1021/ac00061a011 -
Cancer Letters Aug 1992Iron-enriched diets caused an increase of tumor rate in two models of dimethylhydrazine(DMH)-induced colon tumorigenesis in mice. The effect was independent of the time...
Iron-enriched diets caused an increase of tumor rate in two models of dimethylhydrazine(DMH)-induced colon tumorigenesis in mice. The effect was independent of the time the iron-diet was fed, i.e. during DMH-treatment or following the DMH-treatment period. The increase of tumor rate depended on the iron concentration in the diet (0.5-3.5%). The concentration-dependent iron accumulation in the colonic mucosa of mice was paralleled by increments of malonaldehyde contents indicating lipid peroxidation, another factor known to be involved in tumor development. It is suggested that iron exerts cocarcinogenic activity in the DMH-model by stimulating cell proliferation and inducing oxidative stress in the colonic mucosa. This effect of iron is independent of the time of tumor-initiation by DMH, as it is also observed in the period of tumor-promotion/progression after DMH-treatment.
Topics: Animals; Cocarcinogenesis; Colonic Neoplasms; Diet; Food, Fortified; Intestinal Mucosa; Iron; Liver; Male; Mice; Mice, Inbred Strains; Monomethylhydrazine; Rectal Neoplasms
PubMed: 1516040
DOI: 10.1016/0304-3835(92)90239-r -
Cancer Research Jul 1992The methylhydrazines, monomethylhydrazine, 1,1-dimethylhydrazine, and 1,2-dimethylhydrazine, are known carcinogens but only weak mutagens in the Ames test. Chemical...
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.
Topics: 1,2-Dimethylhydrazine; Alkylating Agents; Bacterial Proteins; DNA; DNA Damage; Dimethylhydrazines; Escherichia coli; Escherichia coli Proteins; In Vitro Techniques; Monomethylhydrazine; Mutagens; O(6)-Methylguanine-DNA Methyltransferase; Oxidation-Reduction; Transcription Factors
PubMed: 1617641
DOI: No ID Found -
The Journal of Pharmacy and Pharmacology Jun 1992The effects were examined of four metabolites of the anticancer agent, procarbazine (N-isopropyl-alpha-(2-methyl hydrazino)-p-toluamide hydrochloride) on...
The effects were examined of four metabolites of the anticancer agent, procarbazine (N-isopropyl-alpha-(2-methyl hydrazino)-p-toluamide hydrochloride) on semicarbazide-sensitive amine oxidase (SSAO) and monoamine oxidase-A and -B (MAO-A and -B) activities in rat brown adipose tissue and liver homogenates, respectively. Azoprocarbazine (AZO) and monomethylhydrazine (MMH) inhibited selectively the deamination of benzylamine by SSAO, when compared with their effects on MAO activities. The IC50 values against SSAO, of 32.7 nM (AZO) and 7.0 nM (MMH), were more than three orders of magnitude lower than those exhibited against MAO. Neither isomer of azoxyprocarbazine was an effective inhibitor of rat amine oxidase activities. The inhibition of SSAO by AZO was reversed very slowly by dialysis, in contrast to results seen for MMH. The non-competitive kinetics of MMH and the ability of B24, a rapidly reversible SSAO inhibitor, to protect SSAO against inhibition by MMH are consistent with the view that this compound binds to the enzyme cofactor at, or near, the active site.
Topics: Adipose Tissue, Brown; Amine Oxidase (Copper-Containing); Animals; Benzylamines; Carbon Radioisotopes; In Vitro Techniques; Liver; Monomethylhydrazine; Oxidoreductases Acting on CH-NH Group Donors; Procarbazine; Rats
PubMed: 1359074
DOI: 10.1111/j.2042-7158.1992.tb03653.x -
Carcinogenesis May 1992Electron spin resonance (ESR) analysis combined with the use of 4-pyridyl-1-oxide-t-butyl nitrone (4-POBN) and dibromonitroso benzenesulfonic acid (DBNBS) as...
Electron spin resonance (ESR) analysis combined with the use of 4-pyridyl-1-oxide-t-butyl nitrone (4-POBN) and dibromonitroso benzenesulfonic acid (DBNBS) as spin-trapping agents was used to characterize free radical generation during the metabolism of the anticancer agent procarbazine [N-isopropyl-a-(2-methylhydrazino)-p-toluamide hydrochloride]. The formation of free radical species, identified as methyl radicals, was observed during oxidation of procarbazine in rat liver microsomes and isolated hepatocytes in vitro, as well as in several organs following administration of the drug in vivo. A cytochrome P450-mediated reaction, involving P450IA and IIB isoenzymes, was responsible for the activation process. The metabolic pathway leading to free radical formation was characterized using various procarbazine metabolites and revealed strict analogies with previously published data on methane production from procarbazine. These results supported the identification of the trapped species as methyl free radical and suggested that C-oxidation of azoprocarbazine is the main source of radical intermediates derived from this anticancer drug.
Topics: Animals; Electron Spin Resonance Spectroscopy; Free Radicals; Hydrazones; Liver; Male; Microsomes, Liver; Monomethylhydrazine; NADP; Procarbazine; Rats
PubMed: 1316811
DOI: 10.1093/carcin/13.5.799 -
Blood Mar 1992We have previously shown that excess unpaired alpha- and beta-globin chains in severe alpha- and beta-thalassemia interacting with the membrane skeleton induce different...
We have previously shown that excess unpaired alpha- and beta-globin chains in severe alpha- and beta-thalassemia interacting with the membrane skeleton induce different changes in membrane properties of red blood cells (RBCs) in these two phenotypes. We suggest that these differences in membrane material behavior may reflect the specificity of the membrane damage induced by alpha- and beta-globin chains. To further explore this hypothesis, we sought in vitro models that induce similar membrane alterations in normal RBCs. We found that treatment of normal RBCs with phenylhydrazine produced rigid and mechanically unstable membranes in conjunction with selective association of oxidized alpha-globin chains with the membrane skeleton, features characteristic of RBCs in severe beta-thalassemia. Methylhydrazine, in contrast, induced selective association of oxidized beta-globin chains with the membrane skeleton and produced rigid but hyperstable membranes, features that mimicked those of RBCs in severe alpha-thalassemia. These findings suggest that consequences of oxidation induced by globin chains are quite specific in that those agents that cause alpha-globin chain accumulation at the membrane produce rigid but mechanically unstable membranes, whereas membrane accumulation of beta-globin chains results in rigid but mechanically stable membranes. These in vitro experiments lend further support to the hypothesis that membrane-associated alpha- and beta-chains induce oxidative damage to highly specific different skeletal components and that the specificity of this skeletal damage accounts for the differences in material membrane properties of these oxidatively attacked RBCs and perhaps of alpha- and beta-thalassemic RBCs as well.
Topics: Erythrocyte Deformability; Erythrocyte Membrane; Globins; Humans; Methylphenazonium Methosulfate; Monomethylhydrazine; Oxidation-Reduction; Phenylhydrazines; Thalassemia
PubMed: 1547347
DOI: No ID Found -
Cancer Letters Jan 1992Consumption of false morel (Gyromitra esculenta Fr.) has been associated not only with acute poisoning, but also with a carcinogenic risk. The hydrolysis of...
Consumption of false morel (Gyromitra esculenta Fr.) has been associated not only with acute poisoning, but also with a carcinogenic risk. The hydrolysis of acetaldehyde-N-methyl-N-formylhydrazone (gyromitrin, the main toxic component of false morel) results in the formation of the methylating agents N-methyl-N-formylhydrazine (MFH) and N-methylhydrazine (MMH) (by further hydrolysis of MFH). This study reports traces of N-7-methylguanine (N7MeGu) in liver DNA from mice and a rat treated with gyromitrin. After repeated administration of MMH, N7MeGu was identified in rat liver DNA. In mice exposed to MMH according to a dosing scheme identical to that reported to induce tumours in this species, O6-methylguanine was present in liver and kidney DNA. The results indicate that a relatively low carcinogenic risk is associated with false morel consumption. The risk may be greater in individuals with a decreased detoxification rate (acetylation) of MFH, in whom larger amounts of MMH are formed from gyromitrin.
Topics: Acetaldehyde; Alkylating Agents; Animals; Carcinogens; DNA Damage; Liver; Methylation; Mice; Monomethylhydrazine; Rats
PubMed: 1730140
DOI: 10.1016/0304-3835(92)90175-u -
Toxicology Letters Jul 1991Exposure to monomethylhydrazine (MMH), a common rocket propellant, can cause dose-related central nervous system (CNS) disturbances ranging from tremors to tonic-clonic...
Exposure to monomethylhydrazine (MMH), a common rocket propellant, can cause dose-related central nervous system (CNS) disturbances ranging from tremors to tonic-clonic convulsions to death. MMH inhibits gamma-aminobutyric acid (GABA) synthesis in the CNS. Diazepam (BZ) acts at the GABA receptor site, and it is also here that ivermectin (AVM) is pharmacologically active. Mice were injected with 30 mg/kg MMH. Groups of 12 mice each were then given varying doses of AVM (5, 10 and 15 mg/kg), or AVM + BZ combinations (5 mg/kg AVM with 5 mg/kg BZ, 10 mg/kg AVM with 5 mg/kg BZ). Time to first convulsion and time to death were recorded over the next 7 h and all groups were monitored over the next 7 days. Times to convulsion were not altered with AVM alone, but death was significantly prevented with AVM dosages. A treatment of 10 mg/kg AVM with 5 mg/kg BZ resulted in no seizures or deaths.
Topics: Animals; Diazepam; Injections, Intraperitoneal; Ivermectin; Male; Mice; Mice, Inbred ICR; Monomethylhydrazine; Seizures
PubMed: 1853361
DOI: 10.1016/0378-4274(91)90143-t -
Biochemistry Mar 1991DNA damage induced by methylhydrazines (monomethylhydrazine, 1,1-dimethylhydrazine, and 1,2-dimethylhydrazine) in the presence of metal ions was investigated by a DNA...
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.
Topics: Autoradiography; Copper; DNA Damage; Electron Spin Resonance Spectroscopy; Free Radicals; Manganese; Methylhydrazines; Oxidation-Reduction; Oxygen; Substrate Specificity
PubMed: 1848785
DOI: 10.1021/bi00226a013