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PubMed1976

Inhibition of macromolecular binding of benzo(a)pyrene and inhibition of neoplasia by disulfiram in the mouse forestomach.

Benzo[a]pyrene (BP) administered to female outbred ICR/Ha mice by oral intubation induced neoplasia in the forestomach after 30 weeks in more than 90% of treated animals. However, no tumors occurred at that site if 1% disulfiram was added to the experimental diet. This inhibition of tumor formation was paralleled by a large inhibition of macromolecular binding of [3H]BP and [14C]BP to RNA and protein in the forestomach. The inhibitory effect of specific binding was strongest in the RNA fraction isolated at 8,000 X g for 20 minutes (6 times that of the control) and weakest in the DNA fraction (no significant difference). The highest specific binding was measured in the RNA fraction isolated at 32,000 X g for 120 minutes and the lowest binding in the DNA fraction. The relative distribution of the BP binding was such that greater than 90% of the BP was bound to protein and less than 1% was bound to DNA. Of the total inhibition of BP binding to all the macromolecular species studied, that to protein constituted the largest component (95%). In contrast to the forestomach, no inhibitory effect of BP binding to DNA, RNA, or protein by disulfiram was found in the liver, which remained free of cancer under the experimental conditions employed.

Animals↗
PubMed1989

Fatal liver failure due to disulfiram.

We present the case of a 30-year-old man with disulfiram-induced hepatitis complicated by fatal liver failure. The disease followed a protracted course with an interval of 25 days between the onset of jaundice and the onset of encephalopathy. In this patient, the severity of the liver disease might have been due to reingestion of disulfiram shortly after the onset of jaundice.

Acute Kidney Injury↗
PubMed1979

Liver cell injury (bodies similar to Lafora's) in alcoholics treated with disulfiram (Antabuse).

Inclusions, structurally similar to Lafora's bodies, are described in the liver cells of three chronic alcoholic patients who stopped drinking after disulfiram treatment. The inclusions were strongly positive with PAS and methenamine silver stains. Shikata stain for HBsAg was negative. On electron microscopy the inclusions are not membrane-bound and contain glycogen beta-granules, secondary lysosomes containing lamellar structures, lipid droplets and filaments; the SER was almost completely lost. In the patient least affected, the cells bearing inclusions were predominantly periportal in location, as is usual in Lafora's disease. In the two other patients the change involved the whole lobule. The possibility of an induced carbohydrate metabolic disorder, which could be due to the disulfiram, a drug that interferes with the activity of several hepatic enzymes is discussed. The presence of appearances suggestive of SER breakdown could also be interpreted as a manifestation of 'disuse atrophy' due to alcohol withdrawal.

Adult↗
PubMed1982

Inhibition of aldehyde dehydrogenases in rat brain and liver by disulfiram and coprine.

Rats were treated with either coprine or disulfiram and the inhibition of aldehyde dehydrogenase (ALDH) in liver and brain mitochondria was measured with acetaldehyde, 3,4-dihydroxyphenylacetaldehyde (DOPAL), and succinate semialdehyde at different concentrations. The inhibition pattern was similar for both inhibitors, but the degree of inhibition was lower with disulfiram. The ALDH activity both in the liver and the brain was inhibited at low concentrations of acetaldehyde and DOPAL, but not with succinate semialdehyde. The high-Km enzyme activities with acetaldehyde were not inhibited in liver and brain. The activity at high concentration of DOPAL was inhibited in the liver, but only slightly affected in the brain, suggesting the presence of a brain enzyme with an intermediate Km value for DOPAL. In contrast with the results observed in vivo, it was found that the high-Km activities with acetaldehyde and DOPAL in brain mitochondrial preparations were more sensitive to the inhibitors in vitro than the low-Km activities. Kinetic studies on ALDH preparations from brain and liver mitochondria suggested that acetaldehyde and DOPAL are metabolized by the same low-Km ALDH.

Aldehyde Oxidoreductases↗
PubMed1980

The effects of acetaldehyde and disulfiram on albumin synthesis in the isolated perfused rabbit liver.

Acetaldehyde infusions inhibit albumin synthesis in the liver from fed donors but not in the livers from fasted donors. The inhibition of acetaldehyde metabolism with 4-MP and disulfiram reverses this finding, suggesting that acetaldehyde per se is not the toxic agent. Disulfiram stimulates albumin synthesis in livers from fasted donors, and the presence of acetaldehyde does not prevent this process. The effects of ethanol infusions cannot be explained as due to the presence of acetaldehyde; some intermediate metabolic step may be the basis of the inhibition of albumin production and polysome disaggregation in the presence of ethanol.

Acetaldehyde↗
PubMed1981

Disulfiram-associated hypercholesterolemia.

The rat model is used to verify disulfiram-associated hypercholesterolemia and to determine a mechanism of action. Administration of disulfiram 15 mg/kg/day for 3 wk is associated with a 25% increase in serum cholesterol which is reversible with discontinuance of the drug. The hypercholesterolemia is due in part to a fourfold increase in activity of hepatic HMG-CoA reductase, the rate-limiting step in cholesterol biosyntheses.

Animals↗
PubMedDate not supplied

Disulfiram-ethanol reaction in the rat. 1. Blood alcohol, acetaldehyde, and liver aldehyde dehydrogenase relationships.

Studies were carried out to determine whether the disulfiram-ethanol reaction (DER) in the rat could be correlated with blood acetaldehyde, ethanol, and liver aldehyde dehydrogenase (ALDH) inhibition. Both hypothermia and hypotension were used as indices of the DER. Female Sprague-Dawley rats were given disulfiram (DSF) (100 mg/kg, i.p.) and low and high liver ALDH determined. No effect on high Km ALDH was found. Inhibition of low Km ALDH was dependent on DSF pretreatment time, with significant inhibition observed at 6, 8, and 12 hr following DSF. In rats receiving ethanol only, maximal blood ethanol was reached within 120 min. Blood acetaldehyde was almost undetectable. No change in rat core temperature was observed. In rats pretreated with DSF (100 mg/kg, i.p.) 8 hr before ethanol challenge (1 g/kg, i.p.), a marked increase in blood acetaldehyde was found and remained elevated throughout the temperature and blood pressure monitoring period. Blood ethanol reached a maximum within 90 min and then declined. Maximal hypothermia and hypotension occurred 120 min after ethanol. The administration of the dopamine receptor blocker pimozide (0.5 mg/kg, i.p.) 60 min before ethanol challenge, attenuated the hypothermia and hypotension. Pimozide was effective when given either 60 min before ethanol or 30 min after ethanol. The onset and duration of hypothermia and hypotension during the DER appears to follow the rise and fall of blood ethanol but not blood acetaldehyde.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaldehyde↗
PubMed1992

A review of the pharmacokinetics and pharmacodynamics of disulfiram and its metabolites.

After ingestion, disulfiram (DSF) is rapidly converted, probably in the stomach, to its bis (diethyldithiocarbamato) copper complex. Consequently, absorption and distribution via the gastrointestinal mucosa into the blood might involve both the parent drug and its copper complex. In the blood, both compounds are rapidly degraded to form diethyldithiocarbamic acid (DDC), which is unstable and is further degraded to form diethylamine and carbon disulphide. DDC is also a substrate of phase II metabolism, which involves formation of diethyldithiomethylcarbamate (Me-DDC) and the glucuronic acid of DDC. Me-DDC also undergoes oxidative biotransformation to diethylthiomethylcarbamate (Me-DTC), which is further oxidized to its corresponding sulphoxide and sulphone metabolites. Me-DTC may to act as a suicide inhibitor with a preference for the mitochondrial low Km isozyme of aldehyde dehydrogenases (ALDH 1), whereas the two S-oxidized metabolites, especially the sulfone metabolite, are more potent inhibitors not only of ALDH 1, but also of the cytosolic high Km isozyme of ALDH (ALDH 2). The inhibitory reaction between the enzyme and each of the three metabolites is characterized by a covalent adduct formation, probably with the cysteine residue at the active site of the enzymes. The adduct formed is nonreducible at a physiological concentration of glutathione, and inactivation in the presence of this endogenous tripeptide was increased by action in vitro of the sulphoxide and sulphone metabolites. Those findings are all in concordance with the in vivo observations made on DSF. In human volunteers treated with increasing doses of DSF and challenged with ethanol between each of the dosage periods, the mean plasma concentrations of Me-DTC at steady state were proportional to the DSF doses given. There was also a close relationship between increased oxidative metabolic formation of Me-DTC, high oxidative formation of acetaldehyde, and the full complements of a valid disulfiram ethanol reaction (DER). Consequently, Me-DTC in plasma may not only serve as a marker of the oxidative metabolic function of the liver, but also of the therapeutic effectiveness of the treatment in subjects at steady state. Obviously, there is a need for individual dose-titration regimens. In patients with alcohol-related severe hepatocellular damage, the oxidative P 450 catalyzed formation of the Me-DTC and probably also of its sulfoxide and sulphone metabolites is impaired, and thus inactivation of ALDH activity in the liver appears to be delayed or even completely absent. The consequence for the patient may be an insufficient DER.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetaldehyde↗
PubMed1975

Allergic "contact" dermatitis from disulfiram implants.

Two cases of allergic "contact" dermatitis to implanted disulfiram (tetraethythiuramdisulfide or TETD) pellets are described. This side effect has never been reported before. Other local complications from disulfiram implantations are reviewed.

Adult↗
PubMed1982

Disulfiram treatment of three patients with nickel dermatitis.

Diethyldithiocarbamate chelates nickel and accelerates its excretion in the urine. Disulfiram (Antabuse) splits into two molecules of sodium diethyldithiocarbamate after absorption. Oral administration of disulfiram tablets starting with 50 mg a day with a gradual increase in dosage to 100 mg more than than twice a day readily cleared the eczema in three patients with severe and long-standing nickel contact dermatitis.

Aged↗
PubMed1990

A double-blind placebo controlled study of healthy volunteers given a subcutaneous disulfiram implantation.

A study was carried out to elicit information of the pharmacological effect of implanted disulfiram (DS). Healthy volunteers were randomized to either of two groups; six were given 1 g DS implant and six subjects placebo (PL) implants. Each participant was subjected to one intravenous ethanol challenge before, and six intravenous ethanol challenges as well as one oral ethanol challenge after the implantation. No clinical signs of disulfiram-ethanol reactions (DER) were observed. The intravenous challenges did not result in any significant differences between pre- and post-implantation values for blood acetaldehyde concentrations in the DS group, and these values were not significantly different from the corresponding values in the PL group. However, somewhat higher blood acetaldehyde concentrations were recorded after an oral ethanol dose (0.8 g/kg) in the DS group. In a longitudinal study with oral ethanol challenges after implanted DS, one of three healthy volunteers had a significant higher blood acetaldehyde concentration three weeks after the implantation, while no such tendency was found in any subject tested earlier or later in the post-implantation period. The blood acetaldehyde levels after oral challenges were, however, far too low to produce a DER.

Acetaldehyde↗
PubMed1984

Disulfiram is protective against postischemic cell death in the liver.

The effect of the scavenger compound disulfiram (Antabus) on postischemic cell injury was investigated. Rats were subjected to 90 min of liver ischemia and 3 h of reperfusion. The extent of cell injury was evaluated morphologically by a dye exclusion test and a histochemical stain for calcium. It was found that pretreatment with disulfiram significantly reduced the number of injured cells compared to untreated controls.

Animals↗
PubMed1990

Plasma protein binding of disulfiram and its metabolite diethylthiocarbamic acid methyl ester.

The human plasma protein binding of disulfiram and its metabolite, diethylthiocarbamic acid methyl ester has been studied by an ultrafiltration technique. Both compounds were bound principally to albumin (mean 96.1 and 79.5%) over the ranges 200-800 and 345-2756 nM, respectively. The average number of binding sites was approximately 1 for both substances, whereas the average association constants were 7.1 x 10(4) and 6.1 x 10(3) M-1, respectively. Log P (octanol/water) was 2.81 for disulfiram and 1.85 for diethylthiocarbamic acid methyl ester.

Aldehyde Dehydrogenase↗
PubMed1982

Cure of mice infected with Trypanosoma rhodesiense by cis-diamminedichloroplatinum (II) and disulfiram rescue.

Mice infected with Trypanosoma rhodesiense were treatment concurrently with cis-diamminedichloroplatinum (II) (DDP), disulfiram, and hydration. Most of the mice (92.5 percent) were cured; inoculation of blood or suspensions of brain or heart from these animals did not produce disease in recipient mice. The dose of DDP needed to eliminate the trypanosomes, 3 milligrams per kilogram of body weight per day for 7 days, was lethally toxic unless the animals received disulfiram orally and subcutaneous injections of physiologic saline, which reduced the acute renal necrosis caused by DDP alone. Some mild to moderate reversible renal damage was noted upon pathologic examination of the treated mice.

Animals↗
PubMed1971

Peripheral neuropathy after disulfiram administration.

Peripheral neuropathy and optic neuritis occurring in alcoholics are sometimes due to the toxic effects of disulfiram rather than to alcohol. Unless this is considered in the management of such patients it is likely that administration of the drug will be continued. In the past there have been reports of 16 cases of peripheral neuropathy and six cases of optic neuritis, possibly caused in this way; these reports are reviewed and a further six cases are described. The effects of disulfiram on the nervous system are briefly discussed.

Adult↗
PubMed1992

Blood concentration of carbon disulphide in "normal" subjects and in alcoholic subjects treated with disulfiram.

Assay of free and acid labile carbon disulphide (free and total CS2 respectively) in human blood was performed by gas chromatography/spectrometry. The method used a large dynamic head space volume and a "cryogenic trap". Blood CS2 concentration was measured in 42 subjects not occupationally exposed to CS2 (group A) and in 11 alcoholic subjects (group B) treated with disulfiram. Free CS2 concentration showed a mean value of 261 ng/l in the 42 subjects in group A and 9482 ng/l in eight subjects of group B. Total CS2 concentration was 897 ng/l and 40,084 ng/l in groups A and B respectively. Differences between the groups were highly significant for concentrations of both free and total CS2. Total CS2 concentration was about four times as high as free CS2 concentration in both groups. A significant correlation was found between free and total CS2 concentration both in group A and in group B. In the alcoholic subjects (group B), blood concentrations of both free and total CS2 were related to time of sampling after treatment with disulfiram.

Alcoholism↗