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PubMed1979

Effect of hydrazine exposure on hepatic triacylglycerol biosynthesis.

Acute hydrazine exposure elevated rat liver triacylglycerol content and produced a rapid rise in triacylglycerol production from sn-[1,3-14C]glycerol 3-phosphate by liver homogenate and microsomal fractions. Hydrazine treatment also increased the incorporation of [1,3-14C]glycerol into hepatic triacylglycerol by the intact animal. Homogenates of hepatocyte monolayers exposed to hydrazine in vitro also exhibited an increased capacity to form triacylglycerol from sn-[1,3-14C]glycerol 3-phosphate. Hydrazine-dependent increases in hepatic triacylglycerol production measured in vitro correlated well with an increase in microsomal phosphatidate phosphohydrolase (EC 3.1.3.4) activity. Therefore, the fatty liver associated with hydrazine exposure may be explained in part by a rise in the enzymatic capacity of hepatic triacylglycerol biosynthesis.

Animals↗

PubMed1985

Spin trapping of a free radical intermediate formed during microsomal metabolism of hydrazine.

A radical formed during oxidative metabolism of hydrazine in rat liver microsomes was spin-trapped with alpha-phenyl-t-butylnitrone. The trapped species was identified as hydrazine radical by comparison of its ESR parameters and mass spectrum with those of the adduct formed during CuCl2 catalyzed oxidation of hydrazine. The requirement for oxygen and NADPH in the microsomal oxidation and the occurrence of a typical binding spectrum by difference spectroscopy suggest the involvement of the participation of the cytochrome P-450 enzyme system in the formation of hydrazine radical which must be a precursor of diimide during microsomal oxidation of hydrazine.

Animals↗

PubMed1987

The effects of hydrazine on the phosphatidate phosphohydrolase activity in rat liver.

Injection of hydrazine (0.7 mmole/kg) in the male fasting rats caused an increase in phosphatidate phosphohydrolase (PAP) activity in the soluble fraction of the liver. The increased PAP activity was parallel with a rise in hepatic triacylglycerol (TG) (3.5-fold) and in the catecholamine concentration (3.4-fold) in adrenal glands. Hydrazine also increased serum glucose. The hydrazine-induced increase in PAP activity and TG accumulation was completely prevented by adrenalectomy. The data suggest that increased PAP activity is at least partly responsible for hydrazine-induced fatty liver and that adrenal hormones may take part in the mechanism by which hydrazine exerts its effects on the liver.

Adrenal Glands↗

PubMed1993

Carbon-centered free radical formation during the metabolism of hydrazine derivatives by neutrophils.

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.

1,2-Dimethylhydrazine↗

PubMed1979

Hydrazines as mutagens in a histidine-requiring auxotroph of Salmonella typhimurium.

Hydrazines have been found naturally in tobacco and mushrooms. Other hydrazines are used in industry, medicine, and agriculture. Although about 38 hydrazines are carcinogenic, few, if any, have been tested successfully in rapid bacterial mutagenesis assays. We have utilized a tester strain of Salmonella typhimurium (TA1530) in order to determine the mutagenic activity of a number of hydrazines and related compounds. This strain is thus shown to be effective as a tester organism for the facile detection of hydrazines as mutagens.

Dose-Response Relationship, Drug↗

PubMed1980

The comparative mutagenicities of hydrazine and its mono- and di-methyl derivatives in bacterial test systems.

The mutagenic properties of hydrazine and its mono- and di-methyl derivatives were compared by direct microbial tests with the tryptophan auxotroph Escherichia coli as indicator organism. The methyl- and dimethyl-hydrazine were also tested with metabolic activation both by the Ames plate test and by the host-mediated assay with the histidine auxotroph Salmonella typhimurium tester strains. Only hydrazine and methylhydrazine were mutagenic in direct tests, hydrazine being a far more potent mutagen that methylhydrazine. Neither methylhydrazine nor dimethylhydrazines gave positive results in the Ames tests. In host-mediated assays, symmetrical dimethylhydrazine was clearly mutagenic, whereas methylhydrazine showed marginal mutagenic activity, and unsymmetrical dimethylhydrazine was negative. Evidently the mutagenic actions of different hydrazine derivatives, though these compounds are chemically closely related, depend on different reaction mechanisms.

Drug Evaluation, Preclinical↗

PubMed2005

Comparative metabonomics of differential hydrazine toxicity in the rat and mouse.

Interspecies variation between rats and mice has been studied for hydrazine toxicity using a novel metabonomics approach. Hydrazine hydrochloride was administered to male Sprague-Dawley rats (30 mg/kg, n = 10 and 90 mg/kg, n = 10) and male B6C3F mice (100 mg/kg, n = 8 and 250 mg/kg, n = 8) by oral gavage. In each species, the high dose was selected to produce the major histopathologic effect, hepatocellular lipid accumulation. Urine samples were collected at sequential time points up to 168 h post dose and analyzed by 1H NMR spectroscopy. The metabolites of hydrazine, namely diacetyl hydrazine and 1,4,5,6-tetrahydro-6-oxo-3-pyridazine carboxylic acid (THOPC), were detected in both the rat and mouse urine samples. Monoacetyl hydrazine was detected only in urine samples from the rat and its absence in the urine of the mouse was attributed to a higher activity of N-acetyl transferases in the mouse compared with the rat. Differential metabolic effects observed between the two species included elevated urinary beta-alanine, 3-D-hydroxybutyrate, citrulline, N-acetylcitrulline, and reduced trimethylamine-N-oxide excretion unique to the rat. Metabolic principal component (PC) trajectories highlighted the greater degree of toxic response in the rat. A data scaling method, scaled to maximum aligned and reduced trajectories (SMART) analysis, was used to remove the differences between the metabolic starting positions of the rat and mouse and varying magnitudes of effect, to facilitate comparison of the response geometries between the rat and mouse. Mice followed "biphasic" open PC trajectories, with incomplete recovery 7 days after dosing, whereas rats followed closed "hairpin" time profiles, indicating functional reversibility. The greater magnitude of metabolic effects observed in the rat was supported by the more pronounced effect on liver pathology in the rat when compared with the mouse.

Administration, Oral↗

PubMed1990

Synthesis and evaluation of 1,2,2-tris(sulfonyl)hydrazines as antineoplastic and trypanocidal agents.

Several 1,2,2-tris(sulfonyl)hydrazines, conceived as prodrugs of 1,2-bis(sulfonyl)hydrazines, were synthesized and evaluated for antineoplastic and trypanocidal activities in mice. 1-Methyl-1,2,2-tris(methylsulfonyl)hydrazine emerged as an extremely efficacious antitrypanosomal agent, whereas 1-(2-chloroethyl)-1,2,2-tris(methylsulfonyl)hydrazine was inactive. In contrast, 1-(2-chloroethyl)-1,2,2-tris(methylsulfonyl)hydrazine displayed potent antineoplastic activity, producing several 60-day "cures" of mice bearing leukemia L1210, leukemia P388, or Sarcoma 180. Furthermore, the fact that the tris(sulfonyl) derivatives will not generate isocyanates, which contribute to the host toxicity of nitrosoureas like 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), makes them agents of significant promise in trypanosomal and cancer chemotherapy.

Animals↗

PubMed2001

Metabonomic investigations into hydrazine toxicity in the rat.

The systemic biochemical effects of oral hydrazine administration (dosed at 75, 90, and 120 mg/kg) have been investigated in male Han Wistar rats using metabonomic analysis of (1)H NMR spectra of urine and plasma, conventional clinical chemistry, and liver histopathology. Plasma samples were collected both pre- and 24 h postdose, while urine was collected predose and daily over a 7 day postdose period. (1)H NMR spectra of the biofluids were analyzed visually and via pattern recognition using principal component analysis. The latter showed that there was a dose-dependent biochemical effect of hydrazine treatment on the levels of a range of low molecular weight compounds in urine and plasma, which was correlated with the severity of the hydrazine induced liver lesions. In plasma, increases in the levels of free glycine, alanine, isoleucine, valine, lysine, arginine, tyrosine, citrulline, 3-D-hydroxybutyrate, creatine, histidine, and threonine were observed. Urinary excretion of hippurate, citrate, succinate, 2-oxoglutarate, trimethylamine-N-oxide, fumarate and creatinine were decreased following hydrazine dosing, whereas taurine, creatine, threonine, N-methylnicotinic acid, tyrosine, beta-alanine, citrulline, Nalpha-acetylcitrulline and argininosuccinate excretion was increased. Moreover, the most notable effect was the appearance in urine and plasma of 2-aminoadipate, which has previously been shown to lead to neurological effects in rats. High urinary levels of 2-aminoadipate may explain the hitherto poorly understood neurological effects of hydrazine. Metabonomic analysis of high-resolution (1)H NMR spectra of biofluids has provided a means of monitoring the progression of toxicity and recovery, while also allowing the identification of novel biomarkers of development and regression of the lesion.

Administration, Oral↗

PubMed2005

Integrated metabonomic analysis of the multiorgan effects of hydrazine toxicity in the rat.

Hydrazine is a model toxin that induces both hepatotoxic and neurotoxic effects in experimental animals. The direct biochemical effects of hydrazine in kidney, liver, and brain tissue were assessed in male Sprague-Dawley rats using magic angle spinning nuclear magnetic resonance (NMR) spectroscopy. A single dose of hydrazine (90 mg/kg) resulted in changes to the biochemical composition of the liver after 24 h including an increase in triglycerides and beta-alanine, together with a decrease in hepatic glycogen, glucose, choline, taurine, and trimethylamine-N-oxide (TMAO). From histopathology measurements of liver tissue, minimal to mild hepatocyte alteration was observed in all animals at 24 h. The NMR spectra of the renal cortex at 24 h after dosing were dominated by a marked increase in the tissue concentration of 2-aminoadipate (2-AA) and beta-alanine, concomitant with depletions in TMAO, myo-inositol, choline, taurine, glutamate, and lysine. No alteration to the NMR spectral profile of the substantia nigra was observed after hydrazine administration, but perturbations to the relative concentrations of creatine, aspartate, myo-inositol, and N-acetyl aspartate were apparent in the hippocampus of hydrazine-treated animals at 24 h postdose. No overt signs of histopathological toxicity were observed in either the kidney or the brain regions examined. Elevated alanine levels were observed in all tissues indicative of a general inhibition of alanine transaminase activity. By 168 h postdose, NMR spectral profiles of treated rats appeared similar to those of matched controls for all tissue types indicative of recovery from toxic insult.

Administration, Oral↗

PubMed1981

Anabolic profiles in late-stage cancer patients responsive to hydrazine sulfate.

The anabolic profiles of 59 late-stage cancer patients responsive to hydrazine sulfate were examined; the drug had been given either as a sole agent or added to preexisting therapy to which the patients had become refractory. Most of the patients (79.7%) responded which Indicated Appetite Improvement (IAI), expressed by protocol-code, clinical evaluation and/or direct quantitation. In those patients receiving hydrazine sulfate alone the IAI was 86.1%; in those in whom hydrazine sulfate was added to pre-existing therapy the IAI was 69.6%. Of those cases expressed in direct quantitation the average weight gain for patients receiving hydrazine sulfate alone was 8.2 lbs, whereas the average weight gain for those with pre-existing therapy was 0.6 lbs (p = 0.01). The results suggest the use of hydrazine sulfate as a specific chemotherapy for cancer cachexia, and implicate ineffective concurrent or prior therapy as an apparent negative factor in the generation of anabolic response.

Appetite↗

PubMedDate not supplied

Metabolic fate of hydrazine.

Studies of the disposition of hydrazine administered to mammals have not succeeded in accounting for more than a modest fraction of the dose, nor have the excretory products been completely identified. We have utilized 15N-labeled hydrazine and conventional methods to account for about 75% of single doses of about 0.5 LD50 (1 mmol/kg). In 48 h, about 30% appeared in urine as hydrazine and about 20% emerged as a derivative that is acid-hydrolyzable to hydrazine. About 25% was converted to N2 gas, most of which appeared less than 30 min after administration. The percentage converted to N2 at 4 h increased only slightly with dose between 0.5 and 2.0 mmol/kg. Disappearance of hydrazine from blood was biphasic with half-times of 0.74 and 26.9 h.

Animals↗

PubMed1996

Methylation status of DNA cytosine during the course of induction of liver cancer in hamsters by hydrazine sulfate.

Hydrazine, which is toxic and carcinogenic to rodent liver, has been shown to react with endogenous formaldehyde in the liver to form formaldehyde hydrazone (CH2 = N-NH2), an alkylating intermediate that methylates DNA guanine at the N7- and O6-positions. Studies were conducted to investigate the role of chronic hydrazine-induced hepatotoxicity on DNA maintenance methylation (formation of 5-methyldeoxycytosine) and the development of liver cancer. Male Syrian golden hamsters were given hydrazine sulfate (0, 170, 340 and 510 mg/l) in drinking water for 21 months (average dose 0, 4.2, 6.7 and 9.8 mg/kg body wt hydrazine as the free base). Hepatotoxicity was evaluated histologically, and regenerative DNA synthesis and maintenance methylation were measured as the incorporation of [methyl-14C]thymidine into DNA and the methyl moiety of [methyl-3H]methionine into 5-methyldeoxycytosine in DNA, respectively. Methylguanines were detected in liver DNA at the first observation time of 6 months of treatment; levels of these aberrant bases decreased or became undetectable at 14 months, and increased in a dose-related manner for the remainder of the study. DNA adducts persisted in the highest dose group throughout the study, repeating the results of a similar study previously reported by this laboratory (Bosan et al., Carcinogenesis, 8, 439-444, 1987). Linear regression analysis of thymidine and methionine methyl moiety incorporation into liver DNA suggested impairment of maintenance methylation of DNA (5-methyldeoxycytosine) in the middle and high exposure animals. Hepatic adenomas and hepatocellular carcinomas developed in a dose-related manner and were highly correlated to decreased uptake of radiolabel from methionine into DNA 5-methylcytosine. These results are part of a continuing study on alteration of maintenance methylation during hydrazine induction of liver cancer.

Animals↗

PubMed1996

Changes in methyl-sensitive restriction sites of liver DNA from hamsters chronically exposed to hydrazine sulfate.

Hydrazine sulfate is a genotoxic hepatocarcinogen for the hamster. A study was conducted to follow changes in DNA maintenance methylation in selected genes in liver DNA during the 21-month induction of liver adenomas and hepatocellular carcinomas by demonstrating changes in restriction fragment length polymorphism. Male Syrian golden hamsters were exposed to hydrazine sulfate in the drinking water at three concentrations (170, 340 and 510 mg/l) shown previously to result in a dose-dependent induction of liver tumors. Liver DNA from animals exposed to the high concentration for 6, 12, 16, 20 and 21 months and animals exposed to the low or mid concentration for 21 months was digested with EcoRI, MspI, HindIII or BamHI, or a combination of one of these endonucleases and a methyl-sensitive restriction enzyme, HpaII or HhaI. The DNA digests were subjected to Southern analysis using a c-DNA probe for one of the following genes: DNA methyltransferase (DMT), c-Ha-ras, c-jun, c-fos, and c-myc proto-oncogenes, p53 tumor suppressor gene or gamma-glutamyltranspeptidase. Alteration in DNA restriction by methyl-sensitive endonucleases was detected in four (DMT, c-Ha-ras, p53 and c-jun) of the seven genes examined and as early as 6 months in animals exposed to the highest concentration of hydrazine sulfate; alteration of recognition sites in c-Ha-ras was also detected in DNA from animals exposed for 21 months to the intermediate concentration of hydrazine sulfate. Early changes in recognition sites, presumed to indicate altered methylation status of DNA cytosine and/or guanine mutations, were seen using c-DNA probes for DMT, c-Ha-ras and c-jun; in the p53 tumor suppressor gene alteration of such sites was a late event relevant to appearance of liver adenomas and hepatocellular carcinomas. Evidence for hypomethylation in the p53 and c-jun genes and hypermethylation of the c-Ha-ras and DMT genes is provided. This study supports the induction of site-specific hypomethylation and hypermethylation during the course of hydrazine carcinogenesis.

Animals↗

PubMed1988

Role of formaldehyde hydrazone and catalase in hydrazine-induced methylation of DNA guanine.

Hydrazine is acutely neurotoxic, hepatotoxic and nephrotoxic; it is also carcinogenic to liver and lung in rodents. Administration of hydrazine results in formation of 7-methylguanine and O6-methylguanine in target organ DNA of rats, mice, hamsters and guinea-pigs. It has been suggested that hydrazine reacts with endogenous formaldehyde to form a condensation product which could be metabolized to a methylating agent. Solutions of 0.50 mM hydrazine and formaldehyde have, upon mixing, NMR spectra (300 MHz) consistent with the formation of formaldehyde hydrazone but not other possible condensation products such as tetraformyltriazine or formaldehyde azine. These same solutions evidencing hydrazone formation, when incubated in an in vitro system containing post-mitochondrial (S9), microsomal, cytosolic or mitochondrial cell fractions, resulted in the methylation of DNA guanine; S9 was the most active fraction. Neither the P-450 monooxygenase nor flavin monooxygenase systems appeared to be important in hydrazine/formaldehyde-induced methylation of DNA. However, sodium azide, cyanamide and carbon monoxide all inhibited S9-supported DNA methylation. Bovine liver catalase, a heme-containing cytochrome, readily transformed hydrazine/formaldehyde to a methylating agent. The data support formation of formaldehyde hydrazone as the condensation product of hydrazine and formaldehyde which is rapidly transformed in various liver cell fractions, perhaps by catalase and/or catalase-like enzymes, to a methylating agent.

Amines↗

PubMed1985

Plasma hydrazine concentrations in man after isoniazid and hydralazine administration.

By using a specific sensitive stable-isotope dilution gas chromatography-mass spectrometry (GC-MS) assay, hydrazine was detected in the plasma of eight healthy male volunteer subjects taking isoniazid (300 mg daily) for 2 weeks. Accumulation of hydrazine occurred in slow-acetylator phenotypes. Hydrazine was also detected in the plasma of eight out of 14 hypertensive patients treated chronically with hydralazine (200 mg daily). However, the concentrations of hydrazine observed were much lower than in the isoniazid study and were close to the limit of detection. As hydrazine is hepatotoxic, mutagenic and carcinogenic in animals, its presence in human plasma has important toxicological implications.

Acetylation↗

PubMed2005

Application of a palladium hexacyanoferrate film-modified aluminum electrode to electrocatalytic oxidation of hydrazine.

A palladium hexacyanoferrate (PdHCF) film as an electrocatalytic material was obtained at an aluminum (Al) electrode by a simple electroless dipping method. The modified Al electrode demonstrated a well-behaved redox couple due to the redox reaction of the PdHCF film. The PdHCF film showed an excellent electrocatalytic activity toward the oxidation of hydrazine. The electrocatalytic oxidation of hydrazine was studied by cyclic voltammetry and rotating disk electrode voltammetry techniques. A calibration graph obtained for the hydrazine consisted of two segments (localized at concentration ranges 0.39-10 and 20-75 mM). The rate constant k and transfer coefficient alpha for the catalytic reaction and the diffusion coefficient of hydrazine in the solution D, were found to be 3.11 x 10(3) M(-1) s(-1), 0.52 and 8.03 x 10(-6) cm2 s(-1) respectively. The modified electrode was used to amperometric determination of hydrazine in photographic developer. The interference of ascorbic acid and thiosulfate were investigated and greatly reduced using a thin film of Nafion on the modified electrode. The modified electrode indicated reproducible behavior and a high level of stability during electrochemical experiments, making it particularly suitable for analytical purposes.

Aluminum↗

PubMed1984

The interactions of hydrazine derivatives with rat-hepatic cytochrome P-450.

The ability of different classes of hydrazine derivatives to modify cytochrome P-450 function during turnover as judged by loss of absorbance at 416 nm, loss of CO-reactive cytochrome P-450, or destruction of haem has been studied. Addition of monosubstituted hydrazines to rat-liver microsomes caused considerable loss of CO-reactive cytochrome P-450 and haem destruction; monosubstituted hydrazides caused mainly loss of CO-reactive cytochrome P-450, most likely due to abortive complex formation. Metabolism of 1,1-disubstituted hydrazines by microsomal cytochrome P-450 resulted in loss of CO-reactive cytochrome P-450 only, with no haem destruction. The 1,2-disubstituted hydrazines and hydrazides, procarbazine and iproniazid, acted similarly to the monosubstituted hydrazines, while 1,2-dimethylhydrazine elicited no response, either in observable spectral changes or loss of CO-reactive cytochrome P-450. Synthetic diazene intermediates of phenylhydrazine and N-aminopiperidine reacted rapidly with microsomal cytochrome P-450 to form a spectral intermediate resembling the putative iron porphyrin-diazenyl complex. The decomposition of certain iron porphyrin-diazenyl derivatives apparently leads to destruction of the porphyrin prosthetic group, most likely due to haem alkylation.

Animals↗