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PubMedDate not supplied

The effect of hydrazine sulfate on prostate cancer growth.

Prostate cancer remains the most commonly diagnosed cancer in American males and is the second leading cause of cancer death in this group. Hydrazine sulfate, an inhibitor of gluconeogenesis, has been proposed as a means to improve nutritional status and improve survival in patients with solid tumors. We investigated the effects of hydrazine sulfate on both in vitro and in vivo models of prostate cancer. We examined the cytotoxicity of hydrazine sulfate in both human (LNCaP and PC-3) and animal (MAT-LyLu) prostate cancer cell lines. No growth inhibition was observed. In vivo, hydrazine sulfate did not suppress the growth of implanted Dunning rat prostate MAT-LyLu cells. Hydrazine sulfate does not have activity in these models of prostate cancer and may not be an appropriate therapy for patients with prostate cancer.

Animals↗

PubMed2003

Occupational exposure to hydrazines: treatment of acute central nervous system toxicity.

Exposure to hydrazine and hydrazines' alkylated derivatives is an important occupational health issue, which will increase in significance as space applications increase. Despite their widespread usage as rocket fuels in manned and unmanned space and missile systems, serious exposures to hydrazines are rare. While a significant number of experimental studies were performed in the late 1950s through the mid-1960s, conflicting information exists concerning the most appropriate treatment for these exposures. A cross-sectional study evaluating the most common rocket fuels such as hydrazine; 1,1-dimethylhydrazine (UDMH); mono-methylhydrazine (MMH); and Aerozine-50 against the most commonly suggested therapies, such as pyridoxine, traditional antiseizure therapies, and arginine is needed to clarify the treatment implications for human exposure. Treatments that have been useful for hyperammonemic states, such as those for the six inherited urea cycle defects, have significant potential for the improvement of hydrazine exposure treatment.

Acute Disease↗

PubMed1977

[Mechanism of increasing the effect of antineoplastic agents by hydrazine sulfate].

The results of the in vivo and in vitro experiments indicated that hydrazine sulphate is a new potent inhibitor of the biotransformation of physiologically active compounds, including those with an antitumor effect. It is suggested that hydrazine sulphate renders an inhibitory effect by retarding the access of xenobiotics to microsomal enzymes active centers metabolizing them. The retardation of antitumor compounds biotransformation effected by hydrazine sulphate in vitro enabled the explanation of the enhanced effect of cytostatics, used in combination with hydrazine sulphate in vivo. This fact seems to speak in favour of the perspective clinical application of hydrazine sulphate for potentiation of the antitumor effect of cytostatics.

Animals↗

PubMedDate not supplied

The mitochondrial metabolism of 1,2-disubstituted hydrazines, procarbazine and 1,2-dimethylhydrazine.

Sonication of isolated rat hepatocytes caused a pronounced decrease in the metabolism of biphenyl due to dilution of the cytosolic pool of NADPH, but did not greatly reduce the rate of procarbazine oxidation to its azo derivative. This result suggested the existence of two enzyme systems which can oxidize 1,2-disubstituted hydrazines: an NADPH-dependent (cytochrome P-450) and an NADPH-independent hydrazine oxidase. Upon assaying the various cell fractions of the hepatocyte, it was noted that the NADPH-independent hydrazine oxidase activity was localized in the mitochondria. The reaction was not linked to mitochondrial electron transport, but preincubation of isolated mitochondria with N,N-dimethylpropargylamine markedly inhibited both monoamine oxidase activity (benzylamine and kynuramine deamination) and procarbazine oxidation. During a 15-fold purification of the enzyme, benzylamine oxidase and procarbazine oxidase activity copurified, demonstrating that the rat liver mitochondrial monoamine oxidase can convert procarbazine to its respective azo derivative. 1,2-Dimethyl- and monomethylhydrazine were also metabolized by monoamine oxidase. Procarbazine did not inactivate monoamine oxidase like other hydrazines; this most likely reflects the fact that the oxidation product of the 1,2-disubstituted hydrazines is a stable azo derivative. However, procarbazine is a competitive substrate for the enzyme and may exert some of its toxic neurological effects by altering the metabolism of biogenic amines.(ABSTRACT TRUNCATED AT 250 WORDS)

1,2-Dimethylhydrazine↗

PubMedDate not supplied

A requirement of Pi for the transitory uncoupling of rat liver mitochondria by hydrazine, when beta-hydroxybutyrate is the substrate.

We have recognized an experimental confluence between oxidative phosphorylation and chemical carcinogenesis and, therefore, became interested in the mitochondrial target of hydrazine, which is not only a potential environmental hazard as a carcinogen but is also a likely metabolite of many drugs. Hydrazine induced a Pi dependent transitory uncoupling of rat liver mitochondria when beta-hydroxybutyrate was the substrate. Uncoupling was inhibited by rutamycin; accordingly, the mitochondrial target for nucleophilic hydrazine is an electrophilic site, presumably involving activated Pi. The protective action of ATP2, ADP, PPi and Mg++ was attributed to a conformational change of the phosphorylating enzyme which participated in oxidative phosphorylation. In a mitochondrial system which included ATP gramicidin potassium ion and sulfate, hydrazine, acting as a large cation but not as a nucleophile, blocked mitochondrial swelling and the increment in ATPase activity associated with potassium ion. These data in conjunction with our previous reports dealing with other carcinogens and certain of their derivatives also contribute to an experimental confluence between oxidative phosphorylation and chemical carcinogenesis and are compatible with toxic effects of hydrazine on mitochondria observed previously by others.

Adenosine Diphosphate↗

PubMed1998

A cross-sectional observation of the health effects of hydrazine hydrate and differences of its metabolism by NAT2 polymorphism.

OBJECTIVES: To summarize the results of two studies that attempted to clarify: (1) the health effects of hydrazine hydrate (HH) (N2H4 x H2O: CAS No. 7803-57-8); and (2) the influence of allelic polymorphism of N-acetyltransferase (NAT2) on the metabolism of HH. METHODS: A cross-sectional survey was carried out on 172 male HH-exposed workers and 125 male referent workers at five factories in Japan. The biological half-lives of HH after 1 h of exposure were determined in 12 workers, four workers in each of three NAT2 phenotypes. Clinical examinations were performed and acute and chronic subjective symptoms related to HH were examined by self-administered questionnaires. NAT2 phenotypes were assessed. RESULTS: No hydrazine was detected in either the breathing zones or the urine of the referent workers. The mean hydrazine concentration in the breathing zones, hydrazine and acetylhydrazine in urine, and the cumulative exposure level were 0.0109 ppm, 0.8660 micromol/g x Cr, and 2.80 ppm-years, respectively. There was no difference and no dose-dependent change in the health examination items between HH-exposed and referent workers after adjusting confounding factors, nor in terms of the differences of NAT2 phenotypes. Of 90 subjective symptoms, complaints of nightmares were significantly related to HH exposure. The half-life of urinary hydrazine and acetylhydrazine on rapid, intermediate, and slow phenotypes was 1.68, 3.01, and 4.46 h, respectively. CONCLUSION: This study suggested that current and cumulative exposure to HH did not affect the workers' health, and the half-life of the slow phenotype was longer than those of the rapid and intermediate phenotypes.

Adolescent↗

PubMed2002

Deintercalation of hydrazine-intercalated kaolinite in dry and moist air.

The deintercalation of hydrazine-intercalated kaolinite has been followed using a combination of X-ray diffraction and diffuse reflectance Fourier transform infrared spectroscopy. Upon intercalation of the kaolinite with hydrazine, the kaolinite layers are expanded to 10.66 A and remain expanded for up to 22 h upon exposure to moist air. Only upon deintercalation are the peak at 10.39 A and a minor peak at 9.6 A observed. Complete deintercalation takes up to 18 days more. Upon intercalation with hydrazine an intense band is observed at 3628 cm(-1) and is attributed to the inner-surface hydroxyls hydrogen bonded to the hydrazine, which upon deintercalation decreased in intensity. This rate of deintercalation is affected by the presence or absence of moist air. Deintercalation in the presence of water vapor results in the observation of two additional bands at 3550 and 3598 cm(-1), which are attributed to the hydroxyl stretching modes of adsorbed water during deintercalation. The intensity of NH stretching vibrations observed at 3360, 3300, and 3200 cm(-1) also decrease in intensity with deintercalation time. Changes in the hydroxyl deformation modes of kaolinite in the 915 cm(-1) region and in the HNH deformation modes show strong interactions between the kaolinite surface and the inserting hydrazine molecule.

Journal Article↗

PubMed1999

In Situ Monitoring of the Degradation of Iron Porphyrins by Dioxygen with Hydrazine as Sacrificial Reductant. Detection of Paramagnetic Intermediates in the Coupled Oxidation Process by (1)H NMR Spectroscopy.

The effects of using hydrazine rather than ascorbic acid on the coupled oxidation of (OEP)Fe(II)(py)(2) (OEP is the dianion of octaethylporphyrin, py is pyridine) have been investigated with the goal of directly detecting reactive intermediates during the process of heme degradation by dioxygen. The reaction products, [(OEOP)Fe(II)(py)(2)]Cl and (OEB)Fe(III)(py)(2) (OEOP is the monoanion of octaethyl-5-oxaporphyrin and OEB is the trianion of octaethylbilindione), and their yields are similar to those of the standard coupled oxidation process. The reaction has been monitored in situ in pyridine/dichloromethane mixtures by (1)H NMR spectroscopy. The recently isolated and crystallographically characterized complex, (OEPO)Fe(py)(2) (OEOP is the trianion of octaethyloxaphlorin), has been identified as a key intermediate. Addition of dioxygen to (OEP)Fe(II)(py)(2) in pyridine with hydrazine present also produces two new transient species: (OEPO)Fe(py)(N(2)D(4)) and (OEPO)Fe(N(2)D(4))(2). These complexes have also be produced independently by low-temperature titration of hydrazine into a solution of {(OEPO)Fe}(2). Thus, hydrazine acts as an axial ligand during the early stages of the coupled oxidation process. However, the two hydrazine-containing complexes eventually are converted into (OEPO)Fe(py)(2) before [(OEOP)Fe(II)(py)(2)]Cl and (OEB)Fe(III)(py)(2) are formed. The observations reported here suggest that the coupled oxidation process can be divided into two stages. The first stage involves the meso C-H bond and results in introduction of oxygen at that site with the formation of the three intermediates: (OEPO)Fe(N(2)H(4))(2), (OEPO)Fe(N(2)H(2))(py), and (OEPO)Fe(py)(2). The second stage of the coupled oxidation process involves C-C bond breaking and the conversion of the hydroxylated heme, (OEPO)Fe(py)(2), into the final products, [(OEOP)Fe(II)(py)(2)](+) and (OEB)Fe(III)(py)(2).

Journal Article↗

PubMed1971

On the mechanism and stoichiometry of the oxidation of hydrazine by illuminated chloroplasts.

Hydrazine can support a rapid oxygen uptake in illuminated chloroplasts. The oxygen uptake rate is inhibited by 3-(3,4-dichlorophenyl)-1, 1-dimethylurea but is only slightly increased by added methyl viologen, and little H(2)O(2) is produced. The pH optimum for hydrazine-dependent oxygen uptake is much higher than that of the Hill reaction. Addition of Mn (II) increases the rate of oxygen uptake in the light and causes the reaction to continue in the dark, the dark rate being dependent on the duration of the preceding light period. Flash yield experiments show that at least six electrons are transferred from hydrazine per flash compared to one electron per flash when water is the electron donor.We conclude that most of the oxygen uptake in the presence of hydrazine is due to a direct oxidation of the hydrazine by oxygen which is catalyzed by some factor, possibly Mn (III), produced by chloroplasts in the light. Other artificial electron donors are shown to support such artefactual oxygen uptake to varying extents.

Journal Article↗

PubMed1998

New NO donors with antithrombotic and vasodilating activities, Part 24. Hydrazine derivatives.

Suitable hydrazines like phenylhydrazine (1), N,N-dimethyl hydrazine (4), and N,N-diphenyl hydrazine (5) can be oxidized by hydrogen peroxide at pH 7.4 and 37 degrees C to nitrosohydrogen and further to nitrite and nitrate. The extent of this property is correlated with platelet aggregation inhibiting and antithrombotic effects of these compounds, suggesting that an NO mediated mechanism might be involved. All hydrazines tested and two N-ethoxycarbonyl prodrugs exhibited antihypertensive effects which were not correlated to the above properties. This is especially pronounced in hydralazine (6) and dihydralazine (7) which induced a strong decrease in blood pressure but exhibit neither antiplatelet nor antithrombotic effects. This indicates that the mechanism of the antihypertensive activity is different from that of the antiplatelet activity.

Fibrinolytic Agents↗

PubMed1979

Identification and quantitation of hydrazine in the urine of patients treated with hydralazine.

Hydrazine has been identified by gas chromatography-mass spectrometry in the 0- to 24-hr urine of patients administered hydralazine. With a specific gas chromatographic assay procedure, the amount of hydrazine in the 0- to 24-hr urine was determined in patients treated with various doses of hydralazine. The amount of hydrazine detected in the urine was greater in the slow acetylator phenotype than in the rapid acetylator phenotype. Studies indicated that hydrazine was not produced by chemical breakdown of hydralazine or its known metabolites in urine and therefore was unlikely to be a urinary artefact formed by chemical decomposition in the urine.

Acetylation↗

PubMed1979

Kinetics and mechanism of reaction of m-nitrobenzhydrazide and other hydrazines with acetic acid.

A comprehensive kinetic study was conducted of the reactions of m-nitrobenzhydrazide and some other hydrazines with acetic acid. The overall reaction rate for all of the compounds studied followed pseudo-first-order kinetics. The temperature dependence of the m-nitrobenzhydrazide degradation reaction was determined. The reaction rate dependence on the acetic acid concentration was found to be close to first order. High-pressure liquid chromatography was used extensively in identifying and measuring the appearance or disappearance rates of m-nitrobenzhydrazide degradation products in acetous solution. With m-nitrobenzhydrazide, the major degradation products were N,N'-bis(m-nitrobenzoyl)hydrazine, N-acetyl-N'-m-nitrobenzoylhydrazine, diacetylhydrazine, and hydrazine. The concentration profiles of these products in solution suggested a complex mechanism by which hydrazides react with acetic acid. All eight rate constants at 61 degrees in the suggested mechanism were calculated by an approximation method based on experimental data. The findings in the present study indicate that acetic acid is to be avoided as a solvent for hydrazine derivatives.

Acetates↗

PubMed2004

Mechanisms of hydrazine toxicity in rat liver investigated by proteomics and multivariate data analysis.

A proteomics approach combined with multivariate data analysis was used to examine the hepatotoxic effect of hydrazine in 30 male Sprague Dawley rats, assigned to four treatment groups and two control groups. Liver samples from the individual animals were resolved by two-dimensional differential gel electrophoresis (2-D DIGE) and protein patterns from the 2-D gels were analyzed by principal component analysis (PCA) and partial least squares regression (PLSR). The PCA plot was able to describe the variation in the protein expression related to dose and time, by separation or clustering of different animal groups. PLSR followed by variable selection (Jack-knifing) was used to select proteins that varied significantly in relation to the dose related response of the hydrazine treatment. The 10 up-regulated and 10 down-regulated proteins with highest rank in the PLSR model were identified by mass spectrometry. Hydrazine treatment induced altered expression of proteins related to lipid metabolism, Ca(2+) homeostasis, thyroid hormone pathways and stress response. Several of the identified proteins have not previously been implicated in hydrazine toxicity and may thus be regarded as new potential biomarkers of induced liver toxicity.

Animals↗

PubMed1999

Effects of coenzyme Q10 on changes in the membrane potential and rate of generation of reactive oxygen species in hydrazine- and chloramphenicol-treated rat liver mitochondria.

Effects of CoQ10 and cycloheximide (CHX) on hydrazine- and chloramphenicol (CP)-induced morphological and some functional changes of mitochondria using cultured rat hepatocytes and effects on the process of recovery from CP intoxication using mouse liver were examined. Results obtained are summarized as follows: (1) The formation of megamitochondria induced in the hepatocytes cultured for 22 h in the presence of 2 mM hydrazine or CP (300 microgram/ml) was suppressed by pretreatment of hepatocytes with CoQ10 (1 microM) or CHX (0.5 microgram/ml). This was proved by electron microscopic analysis of mitochondria. (2) Treatment of hepatocytes with hydrazine for 48 h or longer caused decreases in the membrane potential of mitochondria, which were suppressed by CoQ10. (3) Treatment of hepatocytes with hydrazine for 22 h or longer caused remarkable increases in intracellular levels of reactive oxygen species in hepatocytes, which were suppressed by CoQ10. (4) The process of recovery from the CP-induced changes of mitochondria in mouse liver was accelerated by CoQ10 and CHX.

Animals↗

PubMed1998

Identification of hydrazine in commercial preparations of carnosine and its influence on carnosine's antioxidative properties.

Commercial preparations of synthetic carnosine are commonly used by researchers to investigate carnosine's biological functions and potential applications. Our studies on the interaction of synthetic carnosine and aldehydic lipid oxidation products have led to the detection and structural identification of hydrazine, a strong reducing agent. The concentrations of hydrazine in various sources of commercial carnosine were in the range of 0.01-0.20% (w/w). The levels of contaminating hydrazine in commercial carnosine were capable of interfering with the analyses of headspace aldehydes, malonaldehyde, and thiobarbituric acid-reactive substances. Since hydrazine can potentially interfere with lipid oxidation reactions and measurement of lipid oxidation products, it will be necessary to use purified carnosine to reevaluate carnosine's biological and chemical properties.

Aldehydes↗

PubMed1992

Proton NMR spectroscopic studies on the metabolism and biochemical effects of hydrazine in vivo.

The metabolism and disposition of hydrazine and its effects on endogenous metabolites has been studied in rats by the use of high resolution proton NMR spectroscopy of urine. Several metabolites of hydrazine were detected, notably acetyl- and diacetylhydrazine and a cyclised metabolite which results from a hydrazone formed from 2-oxoglutarate and hydrazine. Effects of hydrazine on endogenous metabolites in urine and plasma were also observed; notably a dose-related increase in urinary taurine, a dose-related increase in urinary and plasma lactate, increases in urinary alpha-alanine, beta-alanine, methylamine and a decrease in urinary 2-oxoglutarate. This study has indicated the utility of using high resolution proton NMR spectroscopy to analyse urine for both metabolites and endogenous compounds after exposure of animals to toxic substances.

Animals↗

PubMed1994

Effect of acute and repeated exposure to low doses of hydrazine on hepatic microsomal enzymes and biochemical parameters in vivo.

A single dose of hydrazine (3 mg.kg-1 i.p.) caused hepatic accumulation of triglycerides and depletion of ATP in rats after 9 h. Repeated exposure of rats to hydrazine (approximately equal to 2.5 mg.kg-1 per day) for 10 days resulted in depletion of hepatic reduced glutathione (GSH) and triglycerides. Repeated exposure to hydrazine also caused a significant (time dependent) induction of p-nitrophenol hydroxylase (NPH) activity together with changes in other hepatic microsomal enzymes. These included 7-pentoxyresorufin O-deethylase (PROD) and 7-ethoxyresorufin O-de ethylase (EROD) activity, total cytochrome P450, cytochrome b5 and cytochrome P450 reductase activity. Repeated exposure to lower levels of hydrazine (approximately equal to 0.250 mg.kg-1 per day) caused no significant hepatic biochemical or microsomal changes after 5 or 10 days except for an increase in NPH activity (17%) and liver ATP (15%) after 5 days.

Animals↗

PubMed1996

Role of hydrazine in the mechanism of isoniazid hepatotoxicity in rabbits.

Isoniazid (INH) continues to be a highly effective drug in the chemoprophylaxis and treatment of tuberculosis; however, its use is associated with hepatotoxicity (predominantly hepatic necrosis) in 1-2% of individuals. The INH metabolites, acetylhydrazine and hydrazine, have each been implicated as the causative hepatotoxin in INH-induced hepatotoxicity. Using a model of INH-induced hepatotoxicity in rabbits, in which INH-induced hepatotoxicity manifests as hepatic necrosis, hepatic steatosis (hepatic fat accumulation) and hypertriglyceridaemia (elevated plasma triglycerides), we compared the severity of these measures of toxicity with plasma levels of INH, acetylhydrazine and hydrazine. Plasma INH and acetylhydrazine were not correlated with markers of INH-induced hepatic necrosis or fatty changes. Plasma hydrazine at 32 h was correlated significantly with plasma argininosuccinic acid lyase (ASAL, a sensitive marker of hepatic necrosis) activity as area under the curve (r2 = 0.54, P < 0.002) and log plasma ASAL activity at 48 h after the first dose of INH (r2 = 0.53, p < 0.005), but not with fatty changes. These results show in this model of INH-induced hepatotoxicity in rabbits that hydrazine, and not INH or acetylhydrazine, is most likely involved in the pathogenic mechanism of hepatic necrosis.

Animals↗