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PubMed1984

Influence of disulfiram on the metabolism of N-nitrosodiethylamine.

The effect of disulfiram (DSF) on the biological activity of N-nitrosodiethylamine (NDEA) was studied in vivo. We determined its influence on NDEA level, on NDEA-induced DNA damage and on DNA alkylation in the liver and oesophagus. It was found that 500 mg/kg DSF given 2 h before a single dose of 28 mg/kg NDEA inhibited the metabolism and increased the concentrations of NDEA in the organs, especially in the oesophagus. Consequently, DNA damage and the alkylation of DNA are inhibited in both the liver and the oesophagus.

Alkylation↗
PubMed1984

Effect of disulfiram on N-nitroso-N-methylbenzylamine metabolism. Biochemical aspects.

The present biochemical experiments show that disulfiram inhibits N-nitroso-N-methylbenzylamine metabolism in the rat. More N-nitroso-N-methylbenzylamine may therefore reach extrahepatic tissues. The pathological lesions observed in the lungs in the present system can be explained by the finding that alkylation of lung DNA is increased and repair processes are impaired by enhanced cell proliferation in this organ.

Animals↗
PubMed1984

Role of the respiratory system in metabolism of N-nitrosamines after simultaneous application of disulfiram.

Subsequent to modification of N-nitrosamine metabolism by disulfiram, mucus-producing cells and Clara cells in the respiratory tract are involved increasingly in detoxification as well as in bioactivation of N-nitroso-N-methylbenzylamine and N-nitrosodibutylamine. Overtaxing of these cells or local concentration of antigenic metabolites leads to cytolytic defects in tracheal, bronchial and bronchiolar epithelium, in addition to toxic degenerative lesions. The resulting continuous stimulation of proliferation leads to basal-cell hyperplasia, squamous-cell metaplasia and squamous papillomas. In areas with insufficient differentiation, due to cell proliferation, there is an increased probability that focal mutation, subsequent to alkylation of purine bases, will be passed from one cell generation to the next, with subsequent formation of tumours in the bronchiolo-alveolar region.

Animals↗
PubMedDate not supplied

[Hypotension, mental disorders and changes in catecholamine excretion observed during the administration of disulfiram in a case of pheochromocytoma].

A case of pheocromocytoma treated with disulfiram during ten days in described. Hypotensive and psychiatric effects were observed, which disappeared upon discontinuation of the drug. Urinary amines decreased while the drug was used, and upon interruption of its administration dopamine increased, as a rebound phenomena probably due to availability of tissue dopamine previously blocked by DBH inhibition. The effect of simultaneous administration of alpha-methyldopa is considered.

Adrenal Gland Neoplasms↗
PubMed1981

Other effects of monoaminergic inhibition with 6-hydroxydopamine and of disulfiram on the response to exercise in rats.

A considerable reduction of the run performance (tread-mill test) and a smaller impairment of the swimming capacity occurs in adult rats injected intraperitoneally in the neonatal period with three doses of 50 mg/kg b.w. or 6-hydroxydopamine. In other rats treated i. p. with disulfiram (200 mg/kg) the run performance was significantly reduced. These data, together with histological observations, show the important role of central and peripheral noradrenergic, and not only dopaminergic, mediation in the control of motor behaviour.

Animals↗
PubMed1982

The effect of disulfiram on the carcinogenicity of nitrosamines.

The effect of orally administered disulfiram (DSF) (200 mg/kg diet) on the carcinogenic action of N-nitrosodibutylamine (NDBA) (750 mg/1 drinking water) was investigated in rats. DSF had no effect on the amount of NDBA metabolites in the urine and did not influence the frequency and rate of formation of oesophageal and urinary bladder tumours. While 4 of 25 animals in the group fed only NDBA developed liver tumours, no liver tumours were observed after concurrent application of NDBA and DSF. On the other hand, only the combined application of NDBA and DSF led to the formation of lung tumours (8/27; P = 0.01).

Animals↗
PubMed1979

1,2-Dimethylhydrazine-induced methylation of DNA bases in various rat organs and the effect of pretreatment with disulfiram.

The extent and persistence of methylated purines were determined in DNA of various rat organs following a single s.c. injection of 1,2-di[14C]methylhydrazine. Maximum alkylation of purine bases occurred within 12 hr, with highest concentrations in liver, followed by colon, ileum, and kidney. Over a period of 3 days, O6-methylguanine was removed much more slowly from colon, the principal target organ for carcinogenesis, than from ileum or liver DNA. Dietary pretreatment of rats with disulfiram is known to prevent 1,2-dimethylhydrazine-induced colon carcinogenesis and was found to reduce DNA alkylation to less than 1% of that detected in animals treated with 1,2- di[14C]methylhydrazine alone.

Adenine↗
PubMed1993

Distribution of acetaldehyde in human blood: effects of ethanol and treatment with disulfiram.

The distribution of free and bound acetaldehyde in human blood was studied. Fresh whole blood was precipitated with a perchloric acid (PCA) in saline solution and an aliquot of the crude sample was taken for determination of 'total' acetaldehyde. The remaining sample was centrifuged and the clear supernatant taken for analysis of 'soluble' acetaldehyde. 'Bound' acetaldehyde was calculated by subtracting soluble from total amounts. In samples collected from healthy control subjects, the acetaldehyde level in separated plasma was usually below the limit of detection of the method (0.2 microM), while much higher concentrations (> 2.5 microM) were detected when analyses were carried out on whole blood. In whole blood, about 70% was recovered as bound (i.e. PCA-insoluble) acetaldehyde. The soluble (i.e. free + PCA-soluble) level was higher than that found in separated plasma, suggesting that some acetaldehyde was liberated from the blood cells by PCA treatment. In blood spiked with ethanol, a spontaneous formation of acetaldehyde occurred during the analytical procedure. The artefactual formation increased only the soluble amount, while the bound level remained unchanged. Likewise, in samples drawn from intoxicated subjects, artefactual formation of acetaldehyde was observed in the soluble fraction, while the bound amount was not significantly increased. No significant differences in acetaldehyde levels were found between males and females, nor between healthy control subjects and alcoholic patients undergoing treatment with the aldehyde dehydrogenase inhibitor disulfiram (Antabuse). However, some of the Antabuse patients possessed elevated levels of bound acetaldehyde.

Acetaldehyde↗
PubMed1995

Acute encephalopathy and polyneuropathy after disulfiram intoxication.

A chronic alcoholic who had ingested a very high dose of disulfiram (29 g over a 1-week period) without simultaneous alcohol intake developed an acute encephalopathy and a severe flaccid tetraparesis that worsened over the course of several days, even after the intake of the drug had stopped. Recovery was both slow and incomplete. One year after intoxication, the patient still had distal weakness in the arms and legs, and hypesthesia in the hands and feet.

Adult↗
PubMed1995

Fate and distribution of [14C]S-(N,N-diethyldithiocarbamoyl)-N-acetyl-L-cysteine, an antimutagenic mixed disulfide from disulfiram, in rats.

S-(N,N-Diethyldithiocarbamoyl)-N-acetyl-L-cysteine (AC-DDTC) is a mixed disulfide from disulfiram and N-acetyl-L-cysteine, which possesses putative anticarcinogenic and antimutagenic properties. The present study describes the absorption, distribution, metabolism and excretion of 14C-labeled AC-DDTC in rats. AC-DDTC was well absorbed after oral administration. Based on the excretion of radioactivity in urine, the minimum absorption was about 73%. The rate of absorption was very rapid, with the peak level of radioactivity in plasma after 15 min of administration. Mean Cmax value for N,N-diethyldithiocarbamate (DDTC) after oral dose of AC-DDTC (20 mg/kg) was 3.8 +/- 0.2 nmol/ml at 15 min and the mean residence time was 47.1 +/- 2.8 min. After oral administration of [14C]AC-DDTC, radioactivity was distributed relatively rapidly. Maximum concentrations were observed in the liver (0.443% dose/g), kidneys (0.496% dose/g), oesophagus (0.313% dose/g) and in the adrenals (0.364% dose/g) at 30 min to 1 h after dosing. Liver was the only organ which contains a considerable amount of radioactivity (0.091% dose/g) 24 h after dosing. Two metabolites of AC-DDTC following oral administration were identified in the plasma and liver by GC and HPLC using extractive alkylation technique, namely DDTC and its methyl ester. Urinary excretion was a major route of elimination of radioactivity derived from [14C]AC-DDTC, in that about 73% of the dose was recovered in urine whereas only 14% was found in feces over 7 days.

Acetylcysteine↗
PubMed1996

[Peripheral neuropathies caused by disulfiram].

Disulfirame is a rare cause of peripheral neuropathy in subjects with chronic alcoholism. We report here a case in a 42-year-old man and present the main clinical features and electrophysiological and pathology results. Disulfamine-induced peripheral neuropathy is dose-dependent and never occurs below 250 mg/d (1/2 tables of Espéral*). The pathogenesis is poorly understood.

Adult↗
PubMed1977

[Use of disulfiram in a histochemical study of the influence of different stimuli on the concentration of noradrenaline in brain structures].

With the help of the histochemical fluorescence method the changes in noradrenaline fluorescence of nuc. septi lateralis, nuc. interstitialis striae terminalis and nuc. preoticus medialis during conditioning and unconditioned stimulation were studied. In 135 disulfiram pretreated rats the depletion of noradrenaline fluorescence in the investigated structures was found after electro-stimulation of feet during 5 min., 1 and 2 hours, open-field behavior and reproduction of a conditioned avoidance response. Twelve hours after disulphiram administration the suppression of the open-field behavior and reproduction of the conditioned avoidance response as well as the depletion of noradrenaline fluorescence in the investigated structures were detected.

Animals↗
PubMed1999

Diethylcarbamoylating/nitroxylating agents as dual action inhibitors of aldehyde dehydrogenase: a disulfiram-cyanamide merger.

Benzenesulfohydroxamic acid (Piloty's acid) was functionalized on the hydroxyl group with the N,N-diethylcarbamoyl group, and the hydroxylamine nitrogen was substituted with acetyl (1a), pivaloyl (1b), benzoyl (1c), and ethoxycarbonyl (1d) groups. Only compound 1d inhibited yeast aldehyde dehydrogenase (AlDH) in vitro (IC(50) 169 microM). When administered to rats, 1d significantly raised blood acetaldehyde levels following ethanol challenge, thus serving as a diethylcarbamoylating/nitroxylating, dual action inhibitor of AlDH in vivo. A more potent dual action agent was N-(N, N-diethylcarbamoyl)-O-methylbenzenesulfohydroxamic acid (5c), which was postulated to release diethylcarbamoylnitroxyl (9), a highly potent diethylcarbamoylating/nitroxylating agent, following metabolic O-demethylation in vivo. The dual action inhibition of AlDH exhibited by 1d, and especially 9, constitutes a merger of the mechanism of action of the alcohol deterrent agents, disulfiram and cyanamide.

Acetaldehyde↗
PubMed1987

Inhibition by Salicylhydroxamic Acid, BW755C, Eicosatetraynoic Acid, and Disulfiram of Hypersensitive Resistance Elicited by Arachidonic Acid or Poly-l-Lysine in Potato Tuber.

The hypothesis that arachidonic acid (AA) induction of sesquiterpene accumulation and browning in potato (Solanum tuberosum) is mediated by a lipoxygenase metabolite of AA was tested using lipoxygenase inhibitors. Salicylhydroxamic acid (SHAM) and 3-amino-1-(3-trifluoromethylphenyl)-2-pyrazoline hydrochloride (BW755C) delayed the response to AA. Inhibition by eicosatetraynoic acid (ETYA) was more persistent. These results are consistent with previous reports that SHAM and BW755C are reversible inhibitors of lipoxygenase and easily oxidized by potato while ETYA acts as an irreversible inhibitor. Disulfiram (tetraethylthiuram disulfide) also inhibited AA elicitor activity. SHAM was most effective if applied at the time of AA treatment, having no effect if applied 6 hours afterward. SHAM was effective in the presence of MES or MOPS buffers but not in acetate-buffered or unbuffered solutions; neither BW755C nor ETYA exhibited this restriction. However, SHAM, BW755C, and ETYA also were inhibitors of browning and sesquiterpene accumulation elicited in potato by poly-l-lysine, which, unlike AA, is not a lipoxygenase substrate. SHAM effectiveness also was restricted to 6 hours after treatment with poly-l-lysine. While the results with AA support a role for lipoxygenase, those with poly-l-lysine may be evidence that these compounds are having other effects in potato tissue.

Journal Article↗