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PubMed1987

Metabolism of cyanamide to cyanide and an inhibitor of aldehyde dehydrogenase (ALDH) by rat liver microsomes.

Rat liver microsomes, as well as purified catalase, convert the alcohol deterrent agent, cyanamide, to an active inhibitor of AlDH. Whether this enzymatic activation of cyanamide is mediated primarily by catalase present in the microsomes or involves the cytochrome P-450 enzymes is not known. We now report that cyanide is also a product of the microsomal oxidation of cyanamide. Formation of cyanide from cyanamide and rat liver microsomes was time dependent, reaching maximal levels within 5-10 min. Induction of the cytochrome P-450 enzymes by phenobarbital (PB) pretreatment doubled the yield of cyanide, while SKF-525A blocked this PB-induced increase. Administration of 3-aminotriazole (3-AT) to PB-treated rats inhibited the catalatic activity of their microsomes by 98% and substantially reduced cyanide formation. These results suggest that while catalase is responsible in major part for the oxidation of cyanamide to cyanide by uninduced microsomes, the participation of the hepatic cytochrome P-450 enzymes cannot be ruled out in PB-induced microsomes. We propose a metabolic scheme wherein N-hydroxycyanamide is the intermediate product of cyanamide oxidation, which then decomposes to yield the observed product, cyanide. By deduction, the second product of this decomposition is postulated to be nitroxyl (HNO), which may be the active AlDH inhibitor.

Aldehyde Dehydrogenase↗
PubMed1993

Cyanamide on ethanol intake: how does it really work?

Cyanamide, an aldehyde dehydrogenase inhibitor, has been shown to suppress voluntary ethanol consumption in animals. Studies were carried out to compare the effect of cyanamide on ethanol, saccharin-quinine and water intake in a restricted (10 min) access and in a free-choice nonrestricted access paradigm. An immediate and constant increase in fluid consumption was observed in the restricted access schedule paradigm independent of the fluid tested as cyanamide affected the consumption of all fluids including water. In the nonrestricted access study, cyanamide significantly increased total fluid intake. However, while saccharin-quinine-drinking animals treated with cyanamide demonstrated no change in intake preference, ethanol consumption was suppressed with a concomitant decrease in preference for ethanol. The present findings suggested that cyanamide may possess at least two, paradigm-specific, independent properties. It may enhance the consumption of fluid in general; however, it may also have a specific effect on ethanol intake when animals have continuous ethanol availability.

Alcohol Drinking↗
PubMed1996

Nitrosyl cyanide, a putative metabolic oxidation product of the alcohol-deterrent agent cyanamide.

When incubated with catalase/glucose-glucose oxidase, 13C-labeled cyanamide gave rise not only to 13C-labeled cyanide, but also to 13C-labeled CO2. Moreover, a time-dependent formation of nitrite was observed when cyanamide was oxidized in this system. These results suggested that the initial product of cyanamide oxidation, viz. N-hydroxycyanamide, was being further oxidized by catalase/H2O2 to nitrosyl cyanide (O = N-C = N). Theoretically, nitrosyl cyanide can hydrolyze to the four end-products detected in the oxidative metabolism of cyanamide in vitro, viz. nitroxyl, cyanide, nitrite, and CO2. Accordingly, both unlabeled and 13C-labeled nitrosyl cyanide were synthesized by the low temperature (-40 to -50 degrees) nitrosylation of K-(18-crown-6)cyanide with nitrosyl tetrafluoroborate. The product, a faint blue liquid at this temperature, was transferred as a gas to phosphate-buffered solution, pH 7.4, where it was solvolyzed. Analysis of the headspace by gas chromatography showed the presence of N2O, the dimerization/dehydration product of nitroxyl, while cyanide was detected in the aqueous solution, as measured colorimetrically. [13C]CO2 was analyzed by GC/MS. An oxidative biotransformation pathway for cyanamide that accounts for all the products detected and involving both N-hydroxycyanamide and nitrosyl cyanide as tandem intermediates is proposed.

Alcohol Deterrents↗
PubMed1985

Inhibition of the peroxidatic activity of catalase towards alcohols by the aldehyde dehydrogenase inhibitor cyanamide.

Recent results have suggested that catalase is responsible for activating cyanamide to a metabolite which is a potent inhibitor of aldehyde dehydrogenase. In the present report, cyanamide was shown to inhibit the peroxidatic activity of catalase with alcohols such as ethanol or methanol. Inhibition by cyanamide required a brief incubation period with catalase. Ethanol prevented this inhibition of catalase if added before or at the same time as cyanamide, suggesting that ethanol may protect against the activation of cyanamide by catalase.

Alcohols↗
PubMed1987

Cyanide is a product of the catalase-mediated oxidation of the alcohol deterrent agent, cyanamide.

Cyanide was detected as a product of cyanamide oxidation by bovine liver catalase in vitro under conditions that also produced an active aldehyde dehydrogenase (AlDH) inhibitor. Cyanide formation was directly related to both cyanamide and catalase concentrations and was also dependent on incubation time. The apparent Km for this reaction was 172 microM. Cyanide formation was blocked by ethanol, a known substrate for catalase Compound I. The toxic effects of cyanamide in the dog, a species with limited capacity to conjugate cyanamide by N-acetylation, may be causally related to enhancement of this catalase-mediated pathway for cyanamide metabolism.

Alcohol Deterrents↗
PubMedDate not supplied

Cyanamide given ICV or systemically to the rat alters subsequent alcohol drinking.

Cyanamide or disulfiram serves to suppress volitional intake of alcohol presumably because of the toxic build-up of acetaldehyde dehydrogenase (AIDH). However, the presence of acetaldehyde systemically favors the in vivo synthesis of addictive-like metabolites in the brain which in turn enhance alcohol drinking. The purpose of this investigation, therefore, was to determine whether cyanamide administered to the rat, which did not have access to alcohol during treatment, would nevertheless affect the subsequent preference for alcohol. In the first experiment, cannulae were implanted bilaterally above the cerebral ventricle of 33 adult male Sprague-Dawley rats so that an artificial CSF or a solution of cyanamide could be infused intracerebroventricularly (ICV). Following post-operative recovery, each rat was tested for its alcohol preference by offering it water and a solution of ethyl alcohol which was increased over 8 days from 3-20%. After a single test concentration of alcohol (range of 5-9%) was selected for each individual animal presented with water over a 5-day interval, cyanamide was infused in a volume of 2.5 microliters per side three times daily for 4 days in one of the following total doses: 0.03, 0.1, 0.3, 0.5 or 1.0 mg. A second five-day preference test was run, and 6 weeks following cyanamide infusions a final 3-20% alcohol preference screen was run over 8 days. The results showed that a long-term, dose-dependent increase or decrease in alcohol intake occurred in those rats reactive to the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Drinking↗
PubMed1999

Microsomal formation of nitric oxide and cyanamides from non-physiological N-hydroxyguanidines: N-hydroxydebrisoquine as a model substrate.

The microsomal oxidative transformation of a non-physiological N-hydroxyguanidine was demonstrated for the first time for N-hydroxydebrisoquine as a model substrate (Clement et al., Biochem Pharmacol 46: 2249-2267, 1993). The objective of the present work was to further compare this reaction with the analogous oxidation of arginine via N-hydroxyarginine to citrulline and nitric oxide. The oxidation of N-hydroxydebrisoquine by liver microsomes from rats pretreated with dexamethasone not only produced nitric oxide and the urea, but also the cyanamide derivative as the main metabolite. The low stability of the cyanamide derivative, which easily hydrolyzed to the urea derivative, was noted. The formation of all compounds required cosubstrate and the enzyme source. Experiments with catalase, superoxide dismutase, and H2O2 showed that the O2- formed from the enzyme and the substrate apparently participated in the reaction. While the N-hydroxylation of the guanidine involves the usual monooxygenase activity of cytochrome P-450 (Clement et al., Biochem Pharmacol 46: 2249-2267, 1993), the resultant N-hydroxyguanidine decoupled the monooxygenase. Nitric oxide was detected by the oxyhemoglobin assay. To examine the influence of enzymatically formed nitric oxide on the formation of the metabolites, the N-hydroxydebrisoquine was incubated with SIN-1 as nitric oxide donor under aerobic conditions. It was again possible to detect the cyanamide and urea derivatives, with the latter as main metabolite. It was concluded that the microsomal transformation of N-hydroxydebrisoquine produces a cyanamide and nitric oxide which reacts with N-hydroxydebrisoquine to form the urea derivative. The purely chemical reaction of the unsubstituted N-hydroxyguanidine with nitric oxide gave similar results (Fukuto et al., Biochem Pharmacol 43: 607-613, 1992). In conclusion, similarities (formation of a urea derivative) and differences (formation of a cyanamide derivative) between the physiological oxidation of N-hydroxy-L-arginine by nitric oxide synthases and non-physiological N-hydroxyguanidines by cytochrome P-450 were observed. Furthermore, non-physiological N-hydroxyguanidines can be regarded as nitric oxide donors.

Animals↗
PubMed1999

Effect of cyanamide on toxicity and glutathione depletion in rat hepatocyte cultures: differences between two dichloropropanol isomers.

The effect of aldehyde dehydrogenase inhibition by cyanamide pre-treatment in vitro on dichloropropanol-dependent toxicity and glutathione depletion was investigated in 24 h rat hepatocyte cultures. Cyanamide pre-treatment had no effect on nitrophenol hydroxylase, 7-methoxy-, 7-ethoxy- or 7-benzyloxyresorufin O-dealkylase activities in 24 h cultures from untreated rats, and had no effect on intracellular glutathione content in cultures from untreated rats, or in cultures from isoniazid-treated rats in which cytochrome P4502E1 (CYP2E1) is increased. In cultures from untreated animals the primary alcohol, 2,3-dichloropropanol, was not toxic and did not significantly deplete glutathione. Cyanamide pre-treatment however, potentiated both toxicity and glutathione depletion. Induction of CYP2E1 also potentiated the toxicity of 2,3-dichloropropanol, and in these cultures cyanamide pre-treatment significantly increased both toxicity and glutathione depletion. Cyanamide did not alter the toxicity or glutathione depletion due to the secondary alcohol, 1,3-dichloropropanol, irrespective of CYP2E1 induction. These results indicate that the primary alcohol isomer is metabolised to an aldehyde intermediate which depletes glutathione. Under basal conditions this metabolite appears to be effectively detoxified, but increased CYP2E1 activity and/or decreased aldehyde dehydrogenase activity promotes accumulation of metabolite, and therefore increases glutathione depletion and toxicity.

Aldehyde Dehydrogenase↗
PubMed1992

Embryonic development in the chick following exposure to ethanol, acetaldehyde and cyanamide.

The influence of cyanamide, an inhibitor of aldehyde dehydrogenase, on the embryopathic effects of ethanol and acetaldehyde, was investigated in the chick embryo. Both ethanol and cyanamide significantly increased embryonic mortality, but did not affect embryonic growth, compared to treatment with either ethanol or cyanamide. Acetaldehyde combined with cyanamide increased embryonic mortality and retarded embryonic growth. Cyanamide influence on embryonic development was minimal. The extent of acetaldehyde involvement in ethanol teratogenicity remains unclear from the present findings.

Acetaldehyde↗
PubMed2000

Mechanism of cyanamide hydration catalyzed by carbonic anhydrase II suggested by cryogenic X-ray diffraction.

The three-dimensional structure of a possible intermediate in the hydration reaction of cyanamide to urea catalyzed by human carbonic anhydrase II (hCAII) has been determined by cryocrystallographic techniques. The crystal structure shows that two different adducts are formed under the experimental conditions and that they have different occupancy in the crystal. The high occupancy form consists of a binary hCAII-cyanamide complex where the substrate has replaced the zinc-bound hydroxide anion present in the native enzyme, maintaining the tetrahedral geometry around the metal ion. The second, low-occupancy form consists of a hCAII-cyanamide-water ternary complex where the catalytic zinc ion, still being bound to cyanamide, is approached by a water molecule in a five-coordinate adduct. While the first form can be considered a nonproductive complex, the second form may represent an intermediate state of the catalyzed reaction where the water molecule is about to perform a nucleophilic attack on the zinc-activated cyanamide substrate. The structural evidence is consistent with the kinetic data previously reported about this recently described hydrolytic reaction catalyzed by hCAII, and indicates that a different mechanism with respect to that generally accepted for the physiologic carbon dioxide hydration reaction may be adopted by the enzyme, depending on the substrate chemical properties.

Binding Sites↗
PubMed1999

Daily injections of cyanamide enhance both ethanol-induced locomotion and brain catalase activity.

A role for brain catalase in the mediation of some psychopharmacological effects of ethanol has been proposed. In the present study, we investigated the effects of repeated cyanamide injections on the activity of brain catalase, as well as on the ethanol-induced locomotion of mice. Male Swiss mice were pre-treated with cyanamide (10 mg/kg; three times per day, 5 days) or saline. At different times (2, 3, 6 or 9 days) following this treatment, animals were injected with ethanol. Immediately following this ethanol challenge, animals were placed in the open field chambers and locomotor activity was assessed for 10 min. Results indicated an increase in ethanol-induced locomotion of mice pre-treated with cyanamide 2, 3 or 6 days before the ethanol challenge. Brain catalase activity showed an enhancement at the same time period and the two variables showed a significant correlation. No differences between pre-treatment groups on ethanol blood levels were observed at time of testing. In a second study, the effects of these cyanamide treatment conditions on d-amphetamine-induced locomotor activity were assessed. Results indicated no differences between pre-treatment groups in d-amphetamine-induced locomotion. Thus, these data suggest that repeated daily injections of cyanamide can simultaneously induce both brain catalase and locomotor activity, and that these effects may be strongly related. Furthermore, the present study provides further support for the notion that brain catalase activity may be a factor mediating some of the psychopharmacological effects of ethanol.

Animals↗
PubMed1993

In vivo effects of disulfiram and cyanamide on canine liver aldehyde dehydrogenase isoenzymes as detected by high-performance (pressure) liquid chromatography.

Methods for analysis of aldehyde dehydrogenase isoenzymes using high-performance (pressure) liquid chromatography (HPLC) were used to determine in vivo effects of disulfiram and cyanamide on canine liver aldehyde dehydrogenase (ALDH) isoenzymes. Liver ALDH isoenzymes from control and disulfiram- or cyanamide-treated dogs were separated by ion-exchange HPLC, and enzyme activity was detected using a postcolumn reactor. Two major peaks of ALDH activity (peaks I and II) were detected. Varying the composition of the reaction column reagents resulted in alterations in the elution profiles consistent with the kinetic properties of individual isoenzymes (i.e., ALDH IB in peak I and ALDH IIB in peak II), including estimates of the Km for acetaldehyde and the effects of magnesium ions on ALDH activity. Disulfiram treatment decreased both peaks depending on disulfiram dose and length of treatment, with peak I being more sensitive to inactivation than peak II. Reagents containing MgCl2 (1 mM) decreased peak I and increased peak II compared with EDTA (1 mM) for samples from both control and disulfiram-treated animals. These data are consistent with the assignment of the disulfiram-sensitive isoenzyme (ALDH IB) to peak I and the isoenzyme stimulated by magnesium ions (ALDH IIB) to peak II. In vivo cyanamide treatment produced similar decreases in both peaks to a maximum decrease of approximately 30% of control depending on cyanamide dose. Peak I, however, was more sensitive than peak II to in vitro inactivation by cyanamide, which suggests that cytosolic ALDH in the dog (in contrast to other mammals) is more sensitive to inactivation than mitochondrial ALDH.

Aldehyde Dehydrogenase↗
PubMed1989

Pharmacokinetics of cyanamide in dog and rat.

A pharmacokinetic study of cyanamide, an inhibitor of aldehyde dehydrogenase (E.C. 1.2.1.3) has been made in the beagle dog and Sprague-Dawley rat. Cyanamide plasma levels were determined by a sensitive high performance liquid chromatographic assay, specific for cyanamide. In the dog, i.v. administration of cyanamide at 1, 2 and 4 mg kg-1, produced a dose-dependent pharmacokinetic behaviour. Statistically significant changes were observed in plasma clearance values (12.6 to 19.7 mL kg-1 min-1), half life values (39 to 61 min) and mean residence times (50 to 79 min). Peak plasma concentrations, after oral administration of 4 mg kg-1 were achieved at 30 min and oral bioavailability was about 65%. In the rat after i.v. or oral administration, cyanamide (2 mg kg-1) had a half life of 30 min, a total plasma clearance of 117 mL kg-1 min-1 and a mean residence time of 26 min. Oral bioavailability was about 69%.

Administration, Oral↗
PubMed2005

Differential regulation of proopiomelanocortin (POMC) mRNA expression in hypothalamus and anterior pituitary following repeated cyanamide with ethanol administration.

BACKGROUND/AIM: We have investigated proopiomelanocortin (POMC) mRNA expression in the arcuate nucleus of the hypothalamus (ARC) and the anterior lobe of the pituitary (AL) following repeated cyanamide-ethanol reaction (CER). METHODS: Adult male Sprague-Dawley rats (250-290 gr) were housed in a temperature and humidity controlled environment with free access to food and water. Four experimental groups were used as follows: saline (as control), cyanamide alone, ethanol alone and ethanol with cyanamide. The animals recived daily intraperitoneal injections (i.p.) of cyanamide (10 mg/kg, 60 min before ethanol dosing) with or without ethanol (1g/kg) for 5 consecutive days, and were sacrificed 60 min after the last dosing of ethanol. The results were presented as the mean +/- SEM for each group. All groups within each deta set were compared by one-way ANOVA followed by Fisher PLSD test for multiple comparisons. A value of p < 0.05 was considered significant. RESULTS: The POMC mRNA levels in ARC were significantly decreased with cyanamide compared to the control and ethanol alone (p < 0.05 and p < 0.05 respectively), but increased in AL following repeated CER. CONCLUSION: We speculate that this differential regulation of POMC mRNA expression may be partially involved in the preventive effects on alcohol intake in response to CER.

Animals↗
PubMed1991

Lack of correlation between pharmacokinetic and pharmacodynamic behaviour of cyanamide in man. A preliminary report.

A pharmacokinetic and dynamic study of cyanamide, an inhibitor of aldehyde dehydrogenase (ALDH) used as an adjuvant in the aversive therapy of chronic alcoholism, has been carried out in man after oral administrations. Cyanamide plasma levels were determined by a sensitive and specific high performance liquid chromatographic assay. Blood ALDH activity were estimated after oral administration of 0.3, 1 and 1.5 mg/kg of cyanamide. One i.v. administration of 1 mg/kg was performed in order to determine the absolute bioavailability and the main pharmacokinetic parameters. Elimination half life and total plasma clearance values were 51.7 8.8 min and 14.4 2.7 mL/kg/min respectively. After oral administrations of 0.3, 1 and 1.5 mg/kg a rapid absorption rate was estimated with a Tmax values range of 10.5 to 15.5 min. The extent of absorption was not complete, oral bioavailability being 53%, 70% and 81% respectively. The presence of a first pass-effect is suggested. The inhibitory activity of cyanamide on blood ALDH reached the maximum value 4 h after its administration and decreased progressively throughout six days period. The cyanamide plasma levels time course did not correlated with the pharmacodynamic time course responses.

Administration, Oral↗
PubMed1989

Cyanamide and its calcium form: do they differ with respect to their action on the liver cell? Experimental study in the rat.

Cyanamide is a drug frequently used as aversion therapy in chronic alcoholism. A chronic hepatocytic lesion induced by cyanamide has been described by a member of our team over the last few years. It consists of distinctive cytoplasmic inclusion bodies, similar to those observed in Lafora's disease. The inclusion body-bearing liver cells resemble the ground-glass hepatocytes observed in type B viral infections. This hepatocytic lesion is predictable and reproducible in the rat liver. The high frequency of alcoholic patients with inclusion bodies observed in Spain is striking in contrast with the scarcity of cases published abroad. The medicine commonly used in Spain contains plain cyanamide, while Temposil used in Canada and Dipsan used in Scandinavia contain its calcium form (calcium carbimide). In an attempt to discover if the chemical nature of the drug is an important determinant in the development of the lesion, the present study was carried out using groups of Wistar rats. One group received cyanamide and the other one calcium carbimide. The drug was placed in the stomach via a cannula, daily, at a dose of 16 mg/kg body weight, for 25 weeks. The characteristic inclusion bodies were only found in the group receiving plain cyanamide.

Animals↗
PubMed2005

Carbodiimide production from cyanamide by UV irradiation and thermal reaction on amorphous water ice.

Cyanamide (NH(2)CN), an interstellar molecule, is a relevant molecule in prebiotic chemistry, because it can be converted into urea in liquid water. Carbodiimide (HNCNH), the most stable cyanamide isomer, is able to assemble amino acids into peptides. In this work, using FTIR spectroscopy, we show that carbodiimide can be formed from cyanamide at low temperature (10 K), by a photochemical process in argon matrix, in water matrix, or in solid film. We also report experimental evidence about the carbodiimide formation when cyanamide is condensed at low temperature (50-140 K) on an amorphous water ice surface, or when it is trapped in the water ice. The water ice acts as a catalyst. This isomerization reaction occurs at low temperature (T < 100 K), which agrees with those expected in the interstellar clouds composed of dust grains in which water is the most predominant compound. Finally, the hydrolysis reaction of cyanamide or carbodiimide leading to urea or isourea formation is not observed under our experimental conditions.

Journal Article↗
PubMed1979

Bioassay of calcium cyanamide for possible carcinogenicity.

A bioassay of formulated calcium cyanamide for possible carcinogenicity was conducted by administering the test chemical in feed to F344 rats and B6C3F1 mice. Groups of 50 rats of each sex were administered a commercial formulation containing 63% calcium cyanamide in the diet at one of two doses, either 100 or 200 ppm for the males and either 100 or 400 ppm for the females, for 107 weeks. Groups of 50 mice of each sex were administered the test chemical at one of two doses, either 500 or 2,000 ppm, for 100 weeks. Matched controls consisted of 20 untreated rats and 20 untreated mice of each sex. All surviving animals were killed at the end of administration of the test chemical. Mean body weights of the dosed rats and mice were only slightly lower than those of corresponding controls, except for the low-dose female mice, whose mean body weights were unaffected by the test chemical. Mortality was dose related only in male mice. Survival was 70% or greater in all dosed and control groups of each species and sex at the end of the bioassay, and sufficient numbers of animals were at risk in all groups for the development of late-appearing tumors. Both rats and mice may have been able to tolerate higher doses. No tumors occurred in the dosed rats of either sex at incidences that could clearly be related to administration of the calcium cyanamide. However, in the subchronic studies performed with the rats, calcium cyanamide was found to cause diffuse follicular hyperplasia of the thyroid, with periglandular fibrosis and prominent periglandular vascularity. In male mice, hemangiosarcomas were dose related in the males (P=0.006); however, in direct comparisons, incidences in the individual dosed groups were not significantly higher than those in the control group (controls 1/20 (5%); low-dose 2/50 (4%); high-dose 10/50 (20%)). The incidence of these tumors in historical-control male B6C3F1 mice was (13/323 (4%)), and the highest incidence observed was 2/19 (10%). In female mice, lymphomas or leukemias were dose related (P=0.009), and in a direct comparison the incidence of these tumors in the high-dose group was significantly higher (P=0.006) than that in the control group (controls 1/20 (5%); low-dose 11/46 (24%); high-dose 18/50 (36%)); however, the incidence of the lymphomas or leukemias in historical-control female B6C3F1 mice was 67/324 (21%), suggesting that the incidence of these tumors in the matched-control group of the present bioassay may have been abnormally low. Thus, neither the incidences of hemangiosarcomas of the circulatory system in male mice nor of lymphomas or leukemias in the female mice can clearly be related to administration of the test chemical. It is concluded that under the conditions of this bioassay, the test formulation of calcium cyanamide was not carcinogenic for F344 rats or B6C3F1 mice of either sex.

Journal Article↗