The Actions and Metabolic Fate of Disulfiram

Eneanya, D I; Bianchine, Joseph R.; Duran, D O; Andresen, Brian D.

doi:10.1146/annurev.pa.21.040181.003043

Cited by 209 publications

(109 citation statements)

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“…In these cases, AcH accumulation is ascribed to an insufficient capacity for AcH oxidation. Administration of disulfiram inhibits (8) aldehyde dehydro genase (ALDH) which is the responsible enzyme for AcH oxidation, while in flushing Orientals, the absence of one ALDH isozyme with a high affinity for AcH (low-Km ALDH) has been reported (9, 10).…”

Section: Abstract-alcohol-sensitivementioning

confidence: 99%

Suppression of Acetaldehyde Accumulation by 4-Methylpyrazole in Alcohol-Hypersensitive Japanese

Inoue

Kera

Kiriyama

et al. 1985

Japanese Journal of Pharmacology

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Abstract-Alcohol-sensitiveJapanese subjects with facial flushing and an increase in heart rate during ethanol intoxication exhibited marked individual variation in accumulation of acetaldehyde. This variation correlated well with the intensity of the above mentioned physiological responses.Oral pretreatment with 10 mg/kg 4-methylpyrazole, which inhibited the ethanol elimination rate by 15-25%, strongly suppressed both acetaldehyde accumulation and the associated responses. Under this condition, the sensitivity to acetaldehyde appeared to be reduced, and the correlation between the acetaldehyde level and the physiological responses disap peared.The effectiveness of even a low dose of 4-methylpyrazole suggests its clinical usefulness for alleviation of acute acetaldehyde toxicity in alcohol hypersensitive Japanese individuals as well as in disulfiram-treated alcoholics.

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Section: Abstract-alcohol-sensitivementioning

confidence: 99%

Suppression of Acetaldehyde Accumulation by 4-Methylpyrazole in Alcohol-Hypersensitive Japanese

Inoue

Kera

Kiriyama

et al. 1985

Japanese Journal of Pharmacology

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“…Direct or intentional exposures also occur from therapeutic applications of dithiocarbamates. In addition to the use of disulfiram in alcohol aversion therapy (Eneanya et al, 1981), and N,Ndiethyldithiocarbamate in the treatment of nickel carbonyl intoxication (Sunderman, 1979), a wide range of new medical applications for dithiocarbamates are currently being explored. Investigations have presented support for potential uses of dithiocarbamates in treating cocaine addiction (Sofuoglu and Kosten, 2005), inflammation (Fang et al, 2005), viral infections (Krenn et al, 2005;Si et al, 2005), and as adjuncts for chemotherapy (Bach et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Copper accumulation and lipid oxidation precede inflammation and myelin lesions in N,N-diethyldithiocarbamate peripheral myelinopathy

Viquez

Valentine

Amarnath

et al. 2008

Toxicology and Applied Pharmacology

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Dithiocarbamates have a wide spectrum of applications in industry, agriculture and medicine with new applications being actively investigated. One adverse effect of dithiocarbamates is the neurotoxicity observed in humans and experimental animals. Results from previous studies have suggested that dithiocarbamates elevate copper and promote lipid oxidation within myelin membranes. In the current study, copper levels, lipid oxidation, protein oxidative damage and markers of inflammation were monitored as a function of N,N-diethyldithiocarbmate (DEDC) exposure duration in an established model for DEDC-mediated myelinopathy in the rat. Intraabdominal administration of DEDC was performed using osmotic pumps for periods of 2, 4, and 8 weeks. Metals in brain, liver and tibial nerve were measured using ICP-MS and lipid oxidation assessed through HPLC measurement of malondialdehyde in tibial nerve, and GC/MS measurement of F 2 isoprostanes in sciatic nerve. Protein oxidative injury of sciatic nerve proteins was evaluated through quantification of 4-hydroxynonenal protein adducts using immunoassay, and inflammation monitored by quantifying levels of IgGs and activated macrophages using immunoassay and immunhistochemistry methods, respectively. Changes in these parameters were then correlated to the onset of structural lesions, determined by light and electron microscopy, to delineate the temporal relationship of copper accumulation and oxidative stress in peripheral nerve to the onset of myelin lesions. The data provide evidence that DEDC mediates lipid oxidation and elevation of total copper in peripheral nerve well before myelin lesions or activated macrophages are evident. This relationship is consistent with copper-mediated oxidative stress contributing to the myelinopathy.

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“…DS was reported to be rapidly metabolized to DEDC. Thereafter, DEDC was known to be metabolized reductively into diethylamine and carbon disulfide (12)(13)(14). Thus, the effects of these metabolites were examined (Table 2), but each compound had no effect.…”

Section: Resultsmentioning

confidence: 99%

Protection against Alloxan-Induced Diabetes by Diethyldithiocarbamate and Disulfiram in Mice

Masukawa

Nakanishi

1994

Japanese Journal of Pharmacology

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ABSTRACT-Diethyldithiocarbamate (DEDC, 0.25-2.00 mmol/kg) injected into mice at 0.5 hr prior to alloxan administration dose-dependently protected the mice against the diabetogenic actions of 75 mg/kg alloxan. Disulfiram (DS, 0.50-2.00 mmol/kg), a corresponding disulfide form, also exhibited similar pro tection. The maximum effect of DEDC was found by dosing at 0.5 hr prior to alloxan, and the effect afford ed by DEDC pretreatment persisted up to 3 hr, whereas the effect of DS was exhibited when the compound was given 0.5 hr prior to alloxan. Of the metabolites of DEDC, diethylamine and carbon disulfide had no effect. At 0.5 hr after injection, DEDC alone had a potent increasing ability on blood glucose in a dose dependent manner, but DS was less potent. Mannoheptulose, an antagonist of glucose action at pancreatic p-cells, when given 24 min after DEDC and 6 min before alloxan, eliminated the DEDC-induced protection. Fasted mice did not exhibit hyperglycemia at 0.5 hr after DEDC injection, and alloxan given at that time produced diabetes. These findings indicate that DEDC itself protected mice from alloxan-induced diabetes by the indirect mechanism of producing hyperglycemia at the time of alloxan administration. The anti diabetogenic action of low doses of DS and DEDC, in animals lacking hyperglycemia at the time of alloxan injection, is likely based on a mechanism other than one involving hyperglycemia.

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The Actions and Metabolic Fate of Disulfiram

Cited by 209 publications

References 0 publications

Suppression of Acetaldehyde Accumulation by 4-Methylpyrazole in Alcohol-Hypersensitive Japanese

Suppression of Acetaldehyde Accumulation by 4-Methylpyrazole in Alcohol-Hypersensitive Japanese

Copper accumulation and lipid oxidation precede inflammation and myelin lesions in N,N-diethyldithiocarbamate peripheral myelinopathy

Protection against Alloxan-Induced Diabetes by Diethyldithiocarbamate and Disulfiram in Mice

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