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PubMedDate not supplied

Hepatocarcinogenesis by hydrazine mycotoxins of edible mushrooms.

Two edible mushrooms are known to contain hydrazine analogs. The wild false morel Gyromitra esculenta contains up to 0.3% acetaldehyde methylformylhydrazone and N-methyl-N-formylhydrazine (MFH). The latter chemical, under certain conditions, also yields methylhydrazine. The commonly eaten, cultivated mushroom Agaricus bisporus contains up to 0.04% beta-N-[gamma-L(+)-glutamyl]-4-hydroxymethylphenylhydrazine and 4-hydroxymethylphenylhydrazine. MFH was administered in drinking water continuously for life to Swiss mice and Syrian (golden) hamsters. In both species the compound induced high incidences of benign and malignant hepatocellular neoplasms. Also, methylhydrazine given orally induced a significant incidence of malignant histiocytomas in the livers of hamsters. The N'-acetyl derivative of 4-hydroxymethylphenylhydrazine administered orally to mice gave rise to lung tumors and blood vessel tumors, mainly in the liver. Furthermore, these three compounds produced tumors in various other tissues. Histopathologically, the tumors were classified as benign hepatomas, liver cell carcinomas, angiomas and angiosarcomas of blood vessels, and adenomas and adenocarcinomas of lungs. From representative samples of these neoplasms detailed transmission electron microscopic investigations were also carried out. Since these hydrazine analogs induce tumors in animals and these mushrooms are consumed on a large scale by humans in various parts of the world, their hazardous nature should be considered.

Animals↗
PubMed1980

A field procedure for sampling and analysis of low concentrations of hydrazine in air.

The lowering of the TLV for hydrazine by a factor of 10 indicated the need for a new method for air sampling of this chemical. With introduction of new non-missile applications of hydrazine, the Air Force found a need not only for a method that could be used to determine concentrations less than 0.1 ppm for both long and short term sampling, but also for one that could be readily used for personal exposure monitoring, and one that allowed for field analysis of the collected sample. A method using collection on solid sorbent sampling tubes and analysis by a field colorimetric procedure was developed and proved very satisfactory. The accuracy of this simple and rugged method was well within NIOSH recommendations and the method could be used to determine concentrations well below 0.1 ppm using 1-4L/min personal sampling pumps for less than 10 minute sampling or 0.05-0.20 L/min pumps for sampling over 3 hours.

Air Pollutants↗
PubMed1993

Ethanol and hydrazine sulfate induced chronic hepatic injury in rats: the curative effect of administration of glucogenic amino acids.

There is a widespread belief that when ethanol is fed to rats for a long time, it produces only fatty degeneration without necrosis or fibrosis. In this study, hydrazine sulfate, an inhibitor of low Km ALDH and gluconeogenetic enzymes, was fed with ethanol to rats, and produced more serious pathological changes compared with those found in Lieber's model. Male Sprague-Dawley rats were fed with a low fat liquid diet as a basal diet with ethanol (4%, w/v) and hydrazine sulfate for 4 weeks. At the end of the experiment, plasma aminotransferase levels were found to be elevated. Histological examination showed not only fatty degeneration but also pericellular fibrosis. Therefore, we have evaluated the curative effect of glucogenic amino acids, alanine and glutamine, on this hepatic injury model and found them to be partially protective.

Alanine Transaminase↗
PubMed1995

Evidence for in vivo non-mutagenicity of the carcinogen hydrazine sulfate in target tissues of lacZ transgenic mice.

Transgenic mouse models permit the confirmation of in vitro mutagenicity in vivo without the constraints in the selection of tissues imposed by other in vivo assays. This feature is of particular importance in the determination of mutagenicity in the target tissues of carcinogens, especially those that are in vitro mutagens. Such information is critical in the determination of whether a chemical is carcinogenic via a genotoxic or non-genotoxic mechanism. Hydrazine sulfate is an in vitro mutagen that induces lung and liver tumours in mice. Transgenic mice from strain 40.6 (Mutamouse) were administered single oral doses up to a toxic concentration (400 mg/kg). No dose induced any lacZ mutations in lung, liver or bone marrow. Since the highest single dose used is higher than the cumulative dose that induced tumours in previous studies, it may be that either hydrazine sulfate is genotoxic in target tissues in vivo only when given in multiple doses or that it is a non-genotoxic carcinogen.

Administration, Oral↗
PubMed1998

Contribution of hydrazines-derived alkyl radicals to cytotoxicity and transformation induced in normal c-myc-overexpressing mouse fibroblasts.

Several hydrazine derivatives (HD) tested so far have pharmacological activities, but many also have toxic side effects, including carcinogenesis. Their toxicity has been ascribed to carbocations (via formation of azoxy intermediates), alkyl radicals or reactive oxygen species. Cytotoxicity and transformation by carbocations is widely accepted, but the role of alkyl radicals is still questioned. We have investigated the cytotoxicity of HD to mouse fibroblasts in three activation systems in which enhanced alkyl radical formation is demonstrated by electron spin resonance/spin-trapping. Cytotoxicity was assayed by inhibition of [3H-methyl]thymidine uptake into DNA of Balb/c 3T3 and/or Myc 9E fibroblasts (normal Balb/c 3T3 cells over-expressing the c-myc proto-oncogene). Based on the results obtained in the cytotoxicity assays we also investigated the transforming potential of procarbazine (PCZ) and methylhydrazine (MeH) activated by horseradish peroxidase (HRP) using the Myc 9E cell line, which aims at the activation of a second cooperating oncogene. Our results show that: (i) cytotoxicity of HD to mouse fibroblasts is increased by HRP activation of MeH, phenelzine and PCZ, which displayed enhanced alkyl radical formation, but not of 1,2-dimethylhydrazine (DMH), which did not produce increased alkyl radical formation under these conditions; (ii) cytotoxicity of neutrophil-activated MeH (producing a 10-fold higher concentration of methyl radicals), is more pronounced than DMH; (iii) MeH and DMH activated by prolonged auto-oxidation in 24-h incubations have comparable cytotoxicity and alkyl radical formation; and (iv) PCZ and MeH activation by HRP to alkyl radicals increased the transformation induced in Myc 9E cells. Taken together, our results strongly support a role for hydrazine-derived alkyl radicals in HD-induced cytotoxicity and cell transformation.

3T3 Cells↗
PubMed1992

Release of O-linked sugar chains from glycoproteins with anhydrous hydrazine and pyridylamination of the sugar chains with improved reaction conditions.

A method for preparation of pyridylamino (PA-) derivatives of O-linked sugar chains from glycoproteins was developed. A glycopeptide containing O-linked Gal beta 1-3GalNAc was prepared from fetuin and treated with anhydrous hydrazine followed by N-acetylation of free amino groups. Sugar chains released were pyridylaminated with improved reaction conditions and excess reagents were removed by gel filtration. Gal beta 1-3GalNAc-PA obtained together with PA-Gal as a by-product was quantified by HPLC. Conditions for the hydrazine treatment were investigated and the treatment at 40 degrees C for 350 h gave the best results for releasing O-linked sugar chains. The total yield of Gal beta 1-3GalNAc-PA from the glycopeptide was 53% under the established conditions and that of PA-Gal was 18%. The present method was applied to a glycoprotein, and the expected PA-O-linked sugar chains were obtained. Under these conditions, N-linked sugar chains were also released.

Acetylgalactosamine↗
PubMed1998

Evidence on N-acetyltransferase allele-associated metabolism of hydrazine in Japanese workers.

Hydrazine (N2H4), which has been categorized as a weak carcinogen, is a chemical with the one of the largest production rates in Japan. We have investigated the effects of acetylation phenotypes on the metabolism of hydrazine. Genotypes of N-acetyl transferases, NAT2*, were determined using polymerase chain reaction for 297 male workers. Biological and exposure monitoring were also conducted. The rapid and intermediate acetylators accounted for 45% each, and the slow acetylators accounted for 10%. Biological half-lives were significantly different among the three acetylation phenotypes (analysis of variance, P < 0.05): 3.94+/-1.70 hours for slow acetylators, 2.25+/-0.37 hours for intermediate acetylators, and 1.86+/-0.67 hours for rapid acetylators. Among Japanese, rapid and intermediate acetylators are the major phenotypes, which is in sharp contrast with those among Caucasians. We conclude that biological monitoring should take genetic factors, which may vary dramatically among different populations, into account.

Adult↗
PubMed1977

The influence of hydrazine, phenelzine and nialamide on gluconeogenesis and cell respiration in the perfused guinea-pig liver.

Hydrazine (2 mmol/l) and phenelzine (0.5 mmol/l), which are known to produce hypoglycaemia, inhibit glucose formation from lactate in the perfused guinea-pig liver. The hydrazone formed from pyruvate and phenelzine exerted the same effect at concentrations of only 0.05 mmol/l. It is suggested that the hydrazones are the substances which are effective. All these compounds inhibited pyruvate consumption and decreased CO2 production by the perfused liver which, togeteher with the pattern of hepatic metabolite concentrations, indicate that they diminish pyruvate metabolism. None of them influenced the activities in vitro of pyruvate carboxylase, phosphoenolpyruvate carboxykinase and pyruvate dehydrogenase. The hydrazone compound caused an increase of the ATP/ADP ration at lower concentrations and an opposite effect above 0.5 mmol/l. Nialamide, another hydrazine derivative, also reduced hepatic glucoeogenesis but led to a marked decrease in the hepatic ATP/ADP ratio and liver cell respiration accompanied by a rise in the 3-hydroxybutyrate/acetoacetate ratio.

Animals↗
PubMed1993

Removal of N-terminal formyl groups and deblocking of pyrrolidone carboxylic acid of proteins with anhydrous hydrazine vapor.

Many proteins have a blocked alpha-amino group which renders them inaccessible to sequence analysis by the classical Edman degradation procedure. Blockage typically occurs when the alpha-amino groups are acylated with acetyl or formyl groups or when the N-terminal residue is pyrrolidone carboxylic acid formed by cyclization of glutamine. We have found that N-formyl groups of proteins and peptides can be removed by exposure to hydrazine vapor at -5 degrees C for 8 h. Under these conditions, peptide-bond cleavage or modification of the constituent amino-acid residues does not occur. Deblocking of N-terminal pyrrolidone carboxylate residues by conversion to gamma-hydrazidyl glutamic acid can be achieved by exposure to hydrazine vapor at 20 degrees C for 4 h. These conditions cause partial modification of asparagine and glutamine residues to their corresponding hydrazides, and conversion of arginine residues to ornithine.

Amino Acid Sequence↗
PubMed1982

Mutagenicity and toxicity of carcinogenic and other hydrazine derivatives: correlation between toxic potency in animals and toxic potency in Salmonella typhimurium TA1538.

Eleven hydrazine derivatives and an aromatic amine were examined for mutagenicity and toxicity to Salmonella typhimurium. Phenylhydrazine, 2-nitrophenylhydrazine, 4-nitrophenylhydrazine, 2,4-dinitrophenylhydrazine, p-tolylhydrazine, and 4-nitroaniline were found to be frameshift mutagens (strain TA1538). Benzylhydrazine, m-hydroxybenzylhydrazine, p-hydrazinobenzoic acid, L-tyrosine hydrazide, p-aminobenzoyl hydrazide, and isoniazid were not mutagenic. All chemicals were toxic to strain TA1538. A qualitative correlation was found between the pK of the compounds and their mutagenicity. Relative toxicities of hydrazines to bacteria were found to be closely correlated with the relative toxicities of the same compounds in animals. Described herein is a methodology for the rapid prescreening of chemicals which may be used as drugs for those with a high benefit/risk ratio.

Animals↗
PubMed1984

Occupational exposure to hydrazine and subsequent risk of cancer.

Four hundred and twenty seven men with varying degrees of occupational exposure to hydrazine, a weak animal carcinogen, were studied to see if they provided any evidence of carcinogenicity to man. The observed mortality was close to that expected for lung cancer, other cancers, and all other causes, irrespective of the level of exposure. There were 49 deaths (61.47 expected) from all causes including five deaths from lung cancer (6.65 expected). The results show that no obvious hazards associated with hydrazine exposure have yet appeared but because of the small number of men studied they can only exclude gross hazards.

Chemical Industry↗
PubMed1975

Use of hydrazine sulfate in terminal and preterminal cancer patients: results of investigational new drug (IND) study in 84 evaluable patients.

In a series of 84 various evaluable disseminated cancer patients treated with hydrazine sulfate as a result of a pharmaceutical-sponsored investigational new drug (IND) study, it was found that 59/84 or 70% of the cases improved subjectively and 14/84 or 17% improved objectively. Subjective responses included increased appetite with either weight gain or cessation of weight loss, increase in strength and improved performance status and decrease in pain. Objective responses included measurable tumor regression, disappearance of or decrease in neoplastic-associated disorders and long-term (over 1 year) 'stabilized condition'. Of the overall 59 subjective improvements 25 (42%) had no concurrent or prior (within 3 months) anticancer therapy of any type. Of the 14 objective improvements 7 (50%) had no concurrent or prior anticancer therapy. Of the remaining cases in which there was either concurrent or prior anticancer therapy, improvements occurred only after the addition of hydrazine sulfate to the treatment regimen. Duration of improvement was variable, from temporary to long-term and continuing. Side effects were mild, comprising for the most part low incidences of extremity paresthesias, nausea, pruritus and drowsiness; there was no indication of bone marrow depression.

Drug Evaluation↗
PubMed1975

Hydrazine sulfate and preneoplastic exfoliated cells.

Animal experiments and most encouraging clinical trials substantiate that hydrazine sulfate inhibits the paraneoplastic systemic energy-losing cycle. The question arises: could hydrazine sulfate offer an alternative to surgery for patients with preneoplastic exfoliated cells? Research data indicate that clinical trials are appropriate.

Cell Transformation, Neoplastic↗
PubMed1986

Rifampin-induced release of hydrazine from isoniazid. A possible cause of hepatitis during treatment of tuberculosis with regimens containing isoniazid and rifampin.

The effect of daily administration of rifampin on the direct conversion of isoniazid to isonicotinic acid and hydrazine by isoniazid hydrolase was investigated in 6 slow and 8 rapid acetylators of isoniazid. The proportion of isoniazid metabolized through this direct pathway during the first 6 h was estimated from the ratio of total isonicotinic acid formed to acetylisoniazid in urine after administration of isoniazid or acetylisoniazid. In slow acetylators, this proportion was approximately 3% when isoniazid alone was administered and approximately 6% during the maximal phase of induction caused by the daily administration of rifampin in addition to isoniazid (p less than 0.001); in rapid acetylators, the proportions were considerably less (less than 1 and 2.5%, respectively), suggesting that isoniazid hydrolase was induced by rifampin. The increased formation of hydrazine, a known hepatotoxic agent in animals, could explain the substantially higher frequency of the occurrence of hepatitis in slow than in rapid acetylators among tuberculous patients treated with daily rifampin and isoniazid.

Acetylation↗
PubMedDate not supplied

Possible role of free radical intermediates in hepatotoxicity of hydrazine derivatives.

Hydrazine derivatives constitute a wide group of compounds and have found application in industry, agriculture, and (as therapeutical agents) medicine. In spite of their widely spread use, several hydrazine derivatives are known to exert hepatotoxic effects and are carcinogenic. Free radical species are produced during the hepatic biotransformation of alkylhydrazines by both rat and humans liver microsomes. Cytochrome P-450 dependent monoxygenase system is responsible for the production of these reactive species and specific cytochrome P-450 isoenzymes appear to catalyze the formation of free radical intermediates. Free radicals generated during the metabolism of alkylhydrazines are capable of inducing oxidative stress in isolated hepatocytes and might contribute to the development of cell injury.

Animals↗
PubMed1993

A novel colorimetric method for determination of glycated protein based on 2-keto-glucose release with hydrazine.

We tried to measure glycated proteins by a novel method based on colorimetry of 2-keto-glucose which is released from the glycated protein (ketoamine) on heating with hydrazine. Reaction conditions were optimized with glycated human serum albumin (glc HSA) as a model compound. Ketoamine reacted quantitatively with hydrazine on heating at 100 degrees C for 0.5 h, followed by heating with phenylhydrazine at 60 degrees C for 1 h. Glucose interference with the assay was eliminated by preincubation of the sample with glucose oxidase at 37 degrees C for 0.5 h. Time courses for the coloration of glc HSA and human serum showed a profile similar to that of N-p-tolyl-D-isoglucosamine under optimized reaction conditions. The lower limit for the assay of glc HSA was 0.7 microM. The serum level of glycated proteins measured by the present method correlated well with that (fructoamine value, microM) measured by the conventional method (nitroblue tetrazolium-reducing method) (r = 0.92, n = 35). In conclusion, the present method is a novel, highly sensitive and reliable one for measuring glycated proteins in biological samples.

Colorimetry↗
PubMed1981

Metabolism of isoniazid and free hydrazine formation in isolated rat hepatocytes.

Isoniazid (INH) was incubated with isolated rat hepatocytes, and the amounts of acetyl-INH, monoacetylhydrazine, diacetylhydrazine and hydrazine formed were determined by gas chromatography-mass spectrometry (GC-MS). Subsequent analyses of kinetic parameters of metabolic pathways and enzymological study of rat liver homogenate revealed that hydrazine was formed preferentially from INH, catalyzed by soluble hydrolytic enzymes.

Animals↗
PubMed2003

Characterization of hydrazine derivative: proposed decomposition mechanism and structure elucidation of decomposition compounds.

Decomposition of protected hydrazine diol (1) hemi-oxalate, a key intermediate of the potent indolocarbazole-based DNA topoisomerase I inhibitor (2), was investigated. Spectroscopic analysis revealed that the main decomposition compounds of the hydrazine derivative were a peroxide (3) and an alcohol derivative (4). The peroxide derivative (3) was proposed to form in the presence of oxygen- and/or H(2)O-generated radicals, which was subsequently reduced to the more stable alcohol derivative (4). A plausible decomposition mechanism was proposed and our findings were substantiated by chemical conversion.

Hydrazines↗