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PubMed2001

Engineered nonphosphorylating glyceraldehyde 3-phosphate dehydrogenase at position 268 binds hydroxylamine and hydrazine as acyl acceptors.

Nonphosphorylating nicotinamide adenine dinucleotide (phosphate)-dependent aldehyde dehydrogenases (ALDHs) catalyze the oxidation of aldehydes into either nonactivated acids or CoA-activated acids. The NADP-dependent nonphosphorylating glyceraldehyde 3-phosphate dehydrogenase (GAPN) belongs to the first subclass. It catalyzes the irreversible oxidation of glyceraldehyde 3-phosphate into 3-phosphoglycerate via a two step mechanism in which deacylation is rate-limiting. Recent studies on GAPN from Streptococcus mutans have shown that residue Glu268 plays an essential role only in the deacylation step [Marchal, S., Rahuel-Clermont, S. & Branlant, G. (2000) Biochemistry 39, 3327-3335]. The substitution of Glu268 by alanine or glutamine leads to mutants in which the attacking water molecule involved in the hydrolytic process is poorly activated. Activity can be restored by the presence of hydroxylamine and hydrazine. Neutral and protonated forms of both nucleophiles are recognized by the deacylating subsite of both mutants. pH rate profiles of deacylation show pK(a) values of 6.3 and 8.1 with hydroxylamine and hydrazine, respectively, which are those of the nucleophiles in solution. The increase in enzymatic rate is probably due to a high local concentration and not to a change of the chemical reactivity of both nucleophiles upon their binding within the active site of both mutants. The deacylation subsite of the wild-type also binds hydroxylamine and hydrazine but as inhibitors of the hydrolytic process and not as acyl acceptors. Altogether, the results point out the crucial role of the carboxyl group of Glu268 in preventing nucleophiles, other than water, from binding as efficient acyl acceptors. This may also explain why CoA-dependent ALDHs never possesses a glutamate residue at position 268.

Binding Sites↗
PubMed2004

Surface reaction mechanisms of hydrazine on Si(100)-2 x 1 surface: NH3 desorption pathways.

Multireference as well as single-reference wave functions were adopted to study the surface reaction mechanisms of hydrazine. The initial surface mechanisms resemble those of ammonia and its methyl derivatives. MRMP2 values indicate that the lifetime of initial molecularly adsorbed species should be longer than previously suggested. High energy path as well as low energy path of subsequent surface reactions were found. The theoretical initial surface product of low energy path is consistent with the experimentally suggested structure. Both paths eventually lead to very stable surface products, which are also consistent with the experimentally suggested structures. The reaction channels of the experimentally observed NH3 desorptions were also revealed. It was shown that the high reactivity of hydrazine as compared to ammonia and its methyl derivatives is due to the high nucleophilic ability of the additional nitrogen atom of hydrazine.

Adsorption↗
PubMed2005

1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine: an anticancer agent targeting hypoxic cells.

To target malignant cells residing in hypoxic regions of solid tumors, we have designed and synthesized prodrugs generating the cytotoxic alkylating species 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (90CE) after bioreductive activation. We postulate that one of these agents, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine (KS119), requires enzymatic nitro reduction to produce 90CE, whereas another agent, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(4-nitrobenzyloxy)carbonyl]hydrazine (PNBC), can also be activated by nucleophilic attack by thiols such as glutathione (GSH)/GST. We demonstrated that these agents selectively kill hypoxic EMT6 mouse mammary carcinoma and CHO cells. In hypoxia, 50 microM KS119 produced 5 logs of kill of EMT6 cells without discernable cytotoxicity in air; similar effects were observed with CHO cells. PNBC was less efficacious against hypoxic tumor cells and also had some toxicity to aerobic cells, presumably because of GST/thiol activation, making PNBC less interesting as a selective hypoxic-cell cytotoxin. BALB/c mice with established EMT6 solid tumors were used to demonstrate that KS119 could reach and kill hypoxic cells in solid tumors. To gain information on bioreductive enzymes involved in the activation of KS119, cytotoxicity was measured in CHO cell lines overexpressing NADH:cytochrome b5 reductase (NBR), NADPH:cytochrome P450 reductase (NPR), or NADPH: quinone oxidoreductase 1 (NQO1). Increased cytotoxicity occurred in cells overexpressing NBR and NPR, whereas overexpressed NQO1 had no effect. These findings were supported by enzymatic studies using purified NPR and xanthine oxidase to activate KS119. KS119 has significant potential as a hypoxia-selective tumor-cell cytotoxin and is unlikely to cause major toxicity to well oxygenated normal tissues.

Animals↗
PubMed1982

Studies on hydrazine hepatotoxicity. 1. Pathological findings.

The pathogenesis and factors affecting hydrazine-induced fatty liver have been investigated in rats using histological and ultrastructural examination. A dose of 20 mg hydrazine/kg caused the accumulation of lipid, swelling of mitochondria, and the appearance of microbodies in both periportal and midzonal hepatocytes and in the proximal tubular cells of the kidney. These changes were detectable by light or electron microscopy 24 h after dosing with hydrazine. A dose of 60 mg/kg was the highest dose tolerated for 24 h, but the severity of the fatty liver was similar to that after a dose of 40 mg/kg. The accumulation of lipid droplets and the swelling of mitochondria were detectable by electron microscopy 30 min after dosing, but the accumulation of fat could not be detected by light microscopy until 4 h after dosing. Pretreatment of animals with phenobarbital or piperonyl butoxide respectively reduced and increased the severity of the fatty liver. Pyruvate azine was much less toxic than the parent hydrazine on a molar basis, although some fatty vacuolation was detectable in midzonal hepatocytes.

Animals↗
PubMed1980

Use of a GC concentrator to improve analysis of low levels of airborne hydrazine and unsymmetrical dimethylhydrazine.

New findings from animal studies indicate that there is a serious cancer risk associated with exposures to hydrazines. In June, 1978, NIOSH announced more restrictive occupational exposure levels for these compounds. Adherence to these limits requires improved analytical methodology. This paper describes a modified method for monitoring hydrazine and unsymmetrical dimethylhydrazine in atmospheric samples below the ceiling concentrations recommended by NIOSH. The method utilizes a GC concentrator for which a "trap" (ventable GC precolumn) was prepared and tested. Using this trap, up to 40 microL sample injections (injections much too large for conventional GC work) are effectively chromatographed. Presented are data on the overall efficiency of the method for airborne hydrazine and unsymmetrical dimethylhydrazine in the concentration ranges of 0.02 - 0.67 mg/m3 and 0.04 - 1.04 mg/m3, respectively.

Air Pollutants↗
PubMed1986

Oxidative destruction of hydrazines produces N-nitrosamines and other mutagenic species.

As part of the joint International Agency for Research on Cancer-National Cancer Institute program for the evaluation and development of methods for the degradation of chemical carcinogens, four oxidative techniques for the degradation of hydrazines were investigated. The oxidizing agents used were as follows: sodium hypochlorite, calcium hypochlorite, potassium iodate, and potassium permanganate in sulfuric acid. In each case, at least 99% of the hydrazine initially present was destroyed; however, the potential usefulness of these methods was compromised by the formation (in some reaction mixtures) of carcinogenic N-nitroso compounds and/or unknown mutagenic species. Oxidative degradation of hydrazines is recommended only for the decontamination of glassware and for the treatment of spills, for which reductive degradation methods are not suitable.

Animals↗
PubMed1981

Methylation of liver DNA guanine in hydrazine hepatotoxicity: dose-response and kinetic characteristics of 7-methylguanine and O6-methylguanine formation and persistence in rats.

Fischer 344 or Sprague Dawley rats were fasted overnight and given orally 30--90 mg hydrazine/kg body wt. The presence of 7-methylguanine and O6-methylguanine in liver DNA was demonstrated 5 and 24 h after hydrazine administration using two different analytical techniques. Methylation levels changed little with dose except for the highest dose (ca. LD50) at which the levels doubled. In a time-response study, rats were given 90 mg hydrazine/kg body wt. and killed 0.25 to 96 h later. Both 7-methylguanine and O6-methylguanine were detected quantitatively in liver DNA from rats as early as 15 min after hydrazine administration. After maximum levels of methylguanines had formed, 7-methylguanine was removed from DNA at a rate of approximately 50% in 47 h; the half-life of O6-methylguanine in liver DNA was approximately 13 hr. Three or four, but not one or two, daily administrations of 3 mg hydrazine/kg body wt. also produced detectable levels of 7-methylguanine in rat liver DNA. Neither 7-methylguanine or O6-methylguanine was detected in comparable amounts of liver DNA from control animals. The study confirms the observation that hydrazine administration results in the formation of methylated guanines in liver DNA.

Animals↗
PubMed1978

The degradation of DNA by hydrazine: identification of 3-ureidopyrazole as a product of the hydrazinolysis of deoxycytidylic acid residues.

The reaction of hydrazine with the cytosine residues of DNA yields 3-ureidopyrazole, in approximately 50% yield, in addition to the expected 3-aminopyrazole. This product has been identified by ultraviolet, infrared, nuclear magnetic resonance and mass spectroscopy. A product of the reaction of hydrazine hydrate with cytosine, formulated by others as NN'-di-(3-pyrazolyl) hydrazine, has been identified as 3-ureidopyrazole.

Animals↗
PubMed1975

Enhancement by hydrazine sulfate of antitumor effectiveness of cytoxan, mitomycin C, methotrexate and bleomycin, in walker 256 carcinosarcoma in rats.

Use of hydrazine sulfate potentiates the antitumor action of Cytoxan (cyclophosphamide), Mitomycin C, methotrexate and bleomycin against Walker 256 intramuscular carcinosarcoma in in vivo short-term studies in rats. Experimental data suggest this potentiation by hydrazine sulfate to result from a mechanism of action other than direct cytotoxicity, and further, that combination chemotherapy with hydrazine sulfate and a cytotoxic agent may be useful in the treatment of human cancer.

Animals↗
PubMed1985

Free radical-mediated activation of hydrazine derivatives.

Hydrazines are known to undergo oxidative activation in several enzymatic systems in vitro. Free radicals or carbonium ions have been proposed as active intermediates during such activation. The toxic effects elicited by hydrazines have also been linked to free radical-mediated activation. In this report, we have reviewed the identification of organic free radicals from hydrazines by direct ESR and ESR-spin trapping.

Animals↗
PubMed2004

Simultaneous kinetic-spectrophotometric determination of hydrazine and acetylhydrazine in micellar media using the H-point standard addition method.

The H-point standard addition method (HPSAM), based on a spectrophotometric measurement for the simultaneous determination of hydrazine and acetylhydrazine, is described. This method is based on the difference between the rates of their reactions with N,N-dimethylaminobenzaldehyde (DAB) in the presence of sodium dodecyl sulfate (SDS) in acidic media. The results showed that hydrazine and acetylhydrazine could be determined simultaneously in the range of 0.020 - 0.70 and 0.20 - 5.0 mg L(-1), respectively. Under the working conditions, the proposed method was successfully applied to the simultaneous determination of hydrazine and acetylhydrazine in several synthetic mixtures and plasma and water samples.

Benzaldehydes↗
PubMed2005

Growth inhibition of drug-resistant species of Plasmodium falciparum by domain structured N1,N2-derivatized hydrazines: denticity effects, redox switches, and reductant-driven redox-cycling.

Six analogs of bidentate 1-[pyridoxylidene]-2-phenyl]hydrazine, twelve analogs of N2O-tridentate 1-[pyridoxylidene]-2-[heteroaryl]hydrazine, and four O2N-tridentate analogs of 1-[pyridoxylidene]-2-[heteroaroyl] hydrazines were synthesized and characterized. Their solutions in water and DMSO were assayed in vitro for activity against a chloroquine-resistant species of P. falciparum obtained from Hadassah Hospital Blood Bank in Jerusalem. The O2N-tridentate group was essentially inactive, whereas the bidentate group, with N and O liganding atoms, exhibited slight activity against late-stage trophozoites and schizonts of P. falciparum. The N2O-tridentate group, by contrast, was remarkably active against resistant P. falciparum, highlighting the importance of the Denticity Effect in this system. It is assumed that the pyridoxal-based chelator acts as an iron redox mediator, controlling the first coordination sphere and, therefore, the immediate chemical environment of the iron. Chelation of iron-(II) presumably facilitates its oxidation..The Fe(II) --> Fe(III) intra-electron transfer, may be viewed as a switch ("redox switch"), controlling the thermodynamic stability and kinetic lability of the coordination shell. The redox-switch is accompanied by the appearance of a carbon-based Fe-(III)-chelate radical, capable of donating its free electron to the parasite-DNA, thus causing death. The antimalarial N2O-tridentate Fe(III)-chelates appear to be prone to redox-switch, and tend to be converted into their Fe(II) species, whereas the inactive O2N-tridentate analogs apparently cannot do so.

Animals↗
PubMed1987

Antineoplastic activity of new linear hydrazine derivatives.

A series of hydrazine derivatives was tested for antineoplastic activity. Cyanoacetic acid hydrazide (I), cyanoacetic acid methylhydrazide (II) and N-thioamido-N'-cyano-acethylhydrazine (VI) appeared to be the most active agents against sarcoma 180, Ehrlich carcinoma and Nemeth Kellner lymphoma. The maximum tumor weight inhibition ranged from 70 to 90%. N, N'-bis-cyano-acethylhydrazine (IV) and N-isonicotinoyl-hydrazine (VIII) showed significant antitumor activity in Ehrlich carcinoma and Nemeth Kellner lymphoma systems. None of hydrazine derivatives were active against L1210 leukemia. The most active agents, I, II and VI were further evaluated in leukemia P388, melanoma B16, Lewis lung carcinoma and mammary carcinoma 16/C, and the agent VI was additionally tested in plasmacytoma MP26, colon carcinoma 26 abd Walker carcinosarcoma 256 systems. However, there was no effect with any agent or dose tested against any neoplasm.

Animals↗
PubMed1978

The combined use of L-alpha-methyldopa hydrazine and methyldopa in the treatment of hypertension.

1. The combined use of alpha-methyldopa and L-alpha-methyldopa hydrazine (a peripheral decarboxylase inhibitor) has been studied, in a double-blind cross-over comparison, with alpha-methyldopa and L-alpha-methyldopa hydrazine placebo in the treatment of eight patients with essential hypertension. 2. L-alpha-methyldopa hydrazine did not enhance the antihypertensive effect of alpha-methyldopa. This suggests that because methyldopa can inhibit its own decarboxylation, peripheral decarboxylation is not an important metabolic pathway for methyldopa and elevated brain levels of methyldopa do not necessarily result in elevated brain levels of methyldopamine.

Adult↗
PubMed1979

[Experimental data to substantiate the antitumor action of hydrazine sulfate].

It was found that under the influence of hydrazine sulfate, which in the dosage of 60 mg/kg would induce a 50% suppression of Walker carcinosarcoma in rats, there is the decreased activity of mitochondrial monoamine oxidase and a sharp reduction in the activity of some microsomal phosphatases. Vitamin B6 injection some hours before injecting hydrazine sulfate lessens the rate of suppression of the tumor growth up to 50%. The results obtained indicate that the antitumor effect of hydrazine sulfate may be related to the suppressed monoamine oxidate activity and vitamin B6 deficiency.

Animals↗
PubMed1982

[Selective action of hydrazine sulfate in combination with thiophosphamide on tumor cell mitochondria].

Hydrazine sulfate significantly potentiated antitumor effect of thiophosphamide in experiments on rats with Walker's tumor. The treatment with hydrazine sulfate (60 mg/kg) plus thiophosphamide (1 mg/kg) resulted in suppression of tumor growth up to 90%, the dosage of thiophosphamide being therapeutically ineffective. Following hydrazine sulfate treatment, the activity (pH: 7.0-7.5-7.75) derived from tumors doubled, as compared with control. Similar results were obtained with enzymatic preparations. The activities of DNP-stimulated ATPase and solubilized enzymes in rat liver were not influenced by treatment.

Adenosine Triphosphatases↗
PubMedDate not supplied

[Pharmacokinetics of hydrazine sulfate in intact and tumor-bearing rats].

The pharmacokinetics of hydrazine sulfate was studied in intact and tumor-bearing (sarcoma 45) random-bred rats after intraventricular administration of the drug. To determine hydrazine in biosubstrates, a method was devised, which is based on spectrophotometry of the coloured product formed as a result of interaction with p-dimethylaminobenzaldehyde. Analysis of the pharmacokinetic data with the use of a 4-compartmental model showed appreciable differences in some of the pharmacokinetic parameters of hydrazine sulfate as regards intact and tumor-bearing animals.

Animals↗
PubMed1981

DNA-damaging activity in vivo and bacterial mutagenicity of sixteen hydrazine derivatives as related quantitatively to their carcinogenicity.

Sixteen hydrazine derivatives (hydrazine, 1,1-dimethylhydrazine, 1,2-dimethylhydrazine, phenylhydrazine, procarbazine, isoniazid, isocarboxazid, nialamide, 2,4-dinitrophenylhydrazine, phenelzine, hydralazine, dihydralazine, carbamylhydrazine, mebanazine, iproniazid, and 1-carbamyl-2-phenylhydrazine) were tested for DNA-damaging activity by the alkaline elution technique and for mutagenic activity in the Salmonella-microsome (Ames) test. The first nine compounds listed (56%) were found to induce a significant DNA fragmentation in the liver and/or in the lung of i.p.-treated male Swiss mice. The DNA-damaging potency varied over an approximately 30-fold range. Thirteen of the first 14 compounds listed (81% of the total), isocarboxazid being inactive, were positive in the Ames test, with a broad range of activity towards the five bacterial strains of Salmonella typhimurium used (TA1535, TA100, TA1537. TA1538, and TA98) and of metabolic behavior in the presence of S-9 mix containing rat liver, mouse liver, or mouse lung postmitochondrial preparations from Aroclor-treated animals. The mutagenic potency varied over an almost 7000-fold range. For 11 of the 16 hydrazine derivatives tested, homogeneous carcinogenicity data (induction of pulmonary tumors in mice chronically treated p.o.) were available from literature. Elaboration of these data showed that carcinogenic potency varied over an approximately 1900-fold range. The five most potent carcinogens were all positive in the DNA damage test. Their carcinogenic potency varied over a 130-fold rage and their DNA-damaging potency varied over a 22-fold range. DNA-damaging potency seemed to vary on a more compressed scale, but regression analysis indicated the existence of a strong positive correlation between in vivo DNA-damaging and carcinogenic potencies, while a lack of correlation was found between mutagenic and carcinogenic potencies. There was no correlation between DNA-damaging and mutagenic potencies.

Animals↗