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PubMed1986

Interaction between 1,2-dichloroethane and disulfiram. I. Toxicologic effects.

Inhalation and intraperitoneal (ip) studies with 1,2-dichloroethane (1,2-DCE) using Sprague-Dawley rats fed 0.15% disulfiram (tetraethylthiuram disulfide; Antabuse; DSF) in AIN-76 diet [approx. (79 +/- 11) mg DSF/kg body wt/day] resulted in the observation of a toxic interaction relative to either agent alone. The combination treatment caused testicular atrophy and histopathology in the liver and testes at 1,2-DCE inhalation concentrations greater than 300 ppm (an estimated dose of 194 mg/kg body wt/day) administered 5 days/week for 30 days or at ip doses of 150 mg 1,2-DCE/kg body wt/day over 30 days, 7 days/week. DSF lowered the 1,2-DCE dose at which liver enlargement, decreased liver/body weight ratios, and decreased body weight gains appeared relative to exposure to the 1,2-DCE alone. For the ip study, a decrease in spleen weight also occurred. Testicular atrophy and liver pathology had previously been observed in rats exposed to 20 ppm of ethylene dibromide (EDB) and fed 0.05% DSF in rat chow diet; EDB or DSF alone did not elicit testicular atrophy. These toxic effects indicate that 1,2-DCE may interact with DSF as does EDB, but at a much higher dose.

Aerosols↗
PubMed1975

Investigations in bitro and in vivo, of the effects of disulfiram (Antabuse) on human lymphocyte chromosomes.

Pilinskaya showed that the fungicide ziram induced chrocosome aberrations in the lymphocytes of exposed industrial workers and also in lymphocyte cultures treated in vitro. Ziram is chemically similar to the drug Antabuse (disulfirm) which is used in the treatment of alcoholics. To establish whether disulfirm can also cause chromosome aberrations, we have examined the chrocosomes of lymphocytes from treated and untreated alcoholics and normal controls, and also the chromosomes of lymphocytes treated in vitro. Our results show that disulfirm is 800 times less toxic than ziram and suggest that it is at least 10 000 times less active as an inducer of chromosome aberrations. We found no significant increase in aberrations in vitro or in vivo with disulfiram and conclude taht if it is an inducer of aberrations in lymphoctes then they must be induced with a very low frequency indeed.

Adult↗
PubMed1984

Disulfiram polyneuropathy.

Disulfiram in generally accepted maintenance doses in alcoholism may produce a rather severe polyneuropathy. In addition to the 39 literature cases, 5 personal patients were examined. Detailed clinical findings are given and the frequent permanent sequelae are emphasized. In 2 patients sural nerve biopsies were studied (including electromicroscopical examination) revealing a primary axonal lesion. In the treatment of alcohol addiction one should be aware of this complication.

Adult↗
PubMed1981

Effect of the pretreatment with disulfiram on the toxicity and antitumor activity of 1-(2-hydroxyethyl)-3-(2-chloroethyl)-3-nitrosourea in Sprague--Dawley rats.

Pretreatment with disulfiram (DSF, 1000 mg/kg p.o.) 2 h prior to intraperitoneal injection of 1-(2-hydroxyethyl)3-(2-chloroethyl)-3-nitrosourea (HECNU, NSC 29485) reduced the acute toxicity of HECNU by 50% in Sprague--Dawley rats. Thereafter the effect of this additional treatment on the chemotherapeutic activity of HECNU was investigated. After intraperitoneal transplantation of Yoshida sarcoma ascites cells untreated rats had a median survival time of 8 days. The therapeutic response to a single application of HECNU alone or of DSF followed by HECNU was compared. HECNU was injected intravenously at logarithmically increasing doses from 15 to 61.8 mg/kg. The maximum survival time was increased to about 14 days in rats treated with HECNU. Pretreatment with DSF (1000 mg/kg) resulted in identical or slightly higher life expectancies; it thus reduced the toxic side effects of HECNU without inhibiting its antitumor potency.

Animals↗
PubMed1984

The effects of phenobarbital, bis-p-nitrophenyl phosphate and disulfiram on the hydrolysis of propanidid in Wistar rats.

The short-acting anesthetic propanidid was used in vivo as a model substrate in studies of phenobarbital-inducible carboxylesterases in Wistar rats. Phenobarbital shortened the duration of anesthesia produced by intravenous (25 mg/kg) or intraperitoneal (750 mg/kg) administration of propanidid which was in good agreement with the lowered plasma concentration and the shortened half-life of propanidid in phenobarbital-pretreated rats. The treatment of rats with bis-p-nitrophenyl phosphate or disulfiram with or without phenobarbital-pretreatment prolonged the sleeping time and the half-life of propanidid in plasma.

Animals↗
PubMed1986

5-Hydroxyindoleacetic acid and 5-hydroxytryptophol levels in rat brain: effects of ethanol, pyrazole, cyanamide and disulfiram treatment.

The two serotonin metabolites 5-hydroxyindoleacetic acid (5HIAA) and 5-hydroxytryptophol (5HTOL) were measured in two regions of rat brain (pons medulla and diencephalon) using a gas chromatographic-mass spectrometric (GC-MS) method. Acute ethanol intoxication effected an elevation of 5-hydroxytryptophol levels, while 1 week of treatment with ethanol appeared to have no effect on either metabolite when measured 24 h after the last dose. Disulfiram and cyanamide treatment produced an approximately 2-fold increase in 5-hydroxytryptophol and a slight reduction in 5-hydroxyindole-acetic acid. Pyrazole treatment produced an increase in both metabolites. This effect was, however, counteracted by the simultaneous administration of ethanol.

Animals↗
PubMed1980

The effect of long term treatment with disulfiram on content of cytochrome P-450 and on benzo(a)pyrene monooxygenase activity in microsomes isolated from the rat small intestinal mucosa.

Disulfiram (DS) was administered perorally once a day to rats for 30 days to investigate the effects on cytochrome P-450 content and benzo(a)pyrene (BP) monooxygenase activity in microsomes isolated from the small intestinal mucosa. 50 mg or 100 mg DS/kg body weight caused a dose-related increase in BP monooxygenase activity, whereas the content of cytochrome P-450 was increased at the higher dose only. Similar absorption characteristics of cytochrome P-450 and turnover rates for BP on the basis o f cytochrome P-450 was observed among the different microsomal preparations. The addition of DS or diethyldithiocarbamate (DDTC) to incubates of intestinal microsomes inhibited BP monooxygenase activity. Microsomes isolated from DS-treated rats were however less sensitive to in vitro inhibition by DS.

Animals↗
PubMed1982

Excretion of TTCA in human urine after administration of disulfiram.

2-Thiothiazolidine-4-carboxylic acid (TTCA) was measured in urine of two persons given an oral dose of 250 mg disulfiram. Maximum concentrations up to 0.33 mmol TTCA/mol creatinine were found, 10 to 14 h after dosing. The total amounts of TTCA excreted in urine were 1.8 and 3.5 mumol, respectively, which correspond to 0.2 and 0.4% of the dose.

Adult↗
PubMed1992

An exceptional case of lethal disulfiram-alcohol reaction.

A case of fatal disulfiram-alcohol reaction due to ingestion of ethanol and antabuse is presented. Unusual autopsy findings and toxicological results are described. This case represents a report of corrosion lesion in the lower oesophagus and stomach due to a violent chemical reaction in situ and also the highest blood concentration of acetaldehyde (41 mg/l) ever recorded.

Alcoholic Beverages↗
PubMedDate not supplied

Structure vs. activity in the sulfonylurea-mediated disulfiram-ethanol reaction.

The oral hypoglycemic agents, chlorpropamide (CP) and tolbutamide (TB) are known to elicit a clinical disulfiram-ethanol reaction (DER) when consumed with alcohol. In rats, this DER is manifested in vivo by the elevation of blood acetaldehyde (AcH) levels, a consequence of the inhibition of hepatic aldehyde dehydrogenase (AIDH). Administration of CP or TB to rats (1.0 mmol/kg, IP), followed by ethanol one hour before sacrifice, raised blood AcH levels 12- and 2-times that of control animals, respectively for CP and TB when measured at 3 hours, and 20-fold and 8-fold at 16 hours post drug administration. CP and TB had no effect on AIDH activity when incubated with either intact or osmotically disrupted rat liver mitochondria, indicating that a metabolite of CP or TB is responsible for the inhibition of AIDH in vivo. Hydrolysis products of CP, the 2'-hydroxylated products of CP, tolpropamide and tolethamide, or the 3'-hydroxylated analogs of CP and tolpropamide, were uniformly inactive in elevating ethanol-derived blood AcH. Pretreatment of rats with 3-amino-1,2,4-triazole or SKF-525A had no effect on the elevation of blood AcH mediated by CP or TB, while phenobarbital pretreatment decreased blood AcH by 69%. Although our results clearly indicated that side chain hydroxylation and subsequent oxidation do not play a role in AIDH inhibition by CP or TB, the nature of the side chain attached to the sulfonylurea moiety appears to influence this inhibitory activity in vivo. Thus, the order of activity in the homologous series was, chlorpropamide greater than chlorbutamide greater than chlorethamide much greater than chlormethamide, chlorisopropamide = 0.

Aldehyde Dehydrogenase↗
PubMedDate not supplied

Effect of disulfiram administration on rat brain glutathione metabolism.

Chronic administration of disulfiram (DS) to rats was found to affect glutathione (GSH) metabolism. Glutathione was measured in the rat brain following DS administration. Reduced glutathione was decreased significantly (1.52 +/- 0.3 mumol/g; p < 0.001), with a concomitant increase in oxidised glutathione (GSSG) content (0.12 +/- 0.013 mumol/g; p < 0.001) in the brain as a consequence of DS treatment. However, total glutathione (GSH + GSSG) content of the experimental group did not show any appreciable change. Similar changes were observed in the liver following chronic DS treatment. Brain glutathione reductase (GR) activity was found to be significantly depleted (100 +/- 0.16 mumol/min/mg protein), but glutathione peroxidase (GP) activity was not affected in rats chronically treated with DS. It is reported that the treatment with DS decreases the GSH content, with a concomitant increase in GSSG level, and perturbs the GSH/GSSG redox status, inducing an oxidative stress on the brain. Glutathione reductase implicated in maintaining GSH/GSSG homeostasis by replenishing GSH is also affected by DS potentiating the oxidative damage of the tissue. This effect of DS on glutathione metabolism in the brain would explain some of its known neurotoxic effects.

Animals↗
PubMed2006

Short-term efficacy of Disulfiram or Naltrexone in reducing positive urinalysis for both cocaine and cocaethylene in cocaine abusers: a pilot study.

Cocaine abusers frequently report taking the drug in association with alcohol. This combined intake leads to the synthesis of cocaethylene, an active metabolite with effects similar to those of cocaine, but more prolonged. Since pharmacological effects of cocaethylene may partially account for the habit of cocaine abusers to take the drug in combination with ethanol, a main therapeutic goal in these patients should be making body fluids negative for cocaethylene. This randomized controlled open study conducted on 12 subjects co-abusers of cocaine and alcohol, evaluates the efficacy of a 12-week pharmacological treatment with Disulfiram (DIS) 400mg daily or Naltrexone (NTX) 50mg daily associated with Cognitive Behaviour Therapy (CBT), as compared to CBT alone, in terms of: (i) stay in treatment; (ii) drug-free urinalyses for cocaine and cocaethylene; (iii) reduction of alcohol and cocaine craving. Data presented in this study are restricted to the first 4 weeks of treatment when all the enrolled subjects were still available for examination. In fact, of the 12 subjects enrolled in the study only 4 (33%) completed the 12-week treatment. Of these, three were in the CBT group and one in the NTX/CBT group. Results show that CBT treated subjects remained in treatment longer than those assigned to either DIS/CBT or NTX/CBT therapies. However, during the first 4 weeks of treatment, CBT-group urine tested positive almost always for both cocaine and cocaethylene. In contrast, both DIS/CBT and NTX/CBT treatments were associated to a statistically significant reduction, of positive urinalysis for both cocaine and cocaethylene, with respect to CBT alone. Moreover, across the first 4 weeks of treatment DIS/CBT and NTX/CBT treated subjects maintained lower scores at Visual Analogue Scales (VAS) for both cocaine and alcohol craving than subjects receiving CBT alone. This pilot study suggests that the transient efficacy of pharmacological treatments in maintaining subjects drug free, does not add to the capability of CBT to retain them in treatment.

Adult↗
PubMed2001

Determination of in vivo adducts of disulfiram with mitochondrial aldehyde dehydrogenase.

Extensive use for disulfiram (DSF) has been found in the aversion therapy treatment of recovering alcoholics. Although it is known to irreversibly inhibit hepatic aldehyde dehydrogenase (ALDH), the specific mechanism of in vivo inhibition of the enzyme by the drug has not been determined yet. We have demonstrated in this report a novel, but simple and rapid method for structurally characterizing in vivo derived protein-drug adducts by linking on-line sample processing to HPLC-electrospray ionization mass spectrometry (HPLC-MS) and HPLC-tandem mass spectrometry (HPLC-MS/MS). Employing this approach, rats were administered DSF, and their liver mitochondria were isolated and solubilized. Both native and in vivo DSF-treated mitochondrial ALDH (mALDH) were purified in one step with an affinity cartridge. The in vivo DSF-treated mALDH showed 77% inhibition in enzyme activity as compared with that of the control. Subsequently, the control and DSF-inhibited mALDH were both subjected to HPLC-MS analyses. We were able to detect two adducts on DSF-inhibited mALDH, as indicated by the mass increases of approximately 71 and approximately 100 Da. To unequivocally determine the site and structure of these adducts, on-line pepsin digestion-HPLC-MS and HPLC-MS/MS were performed. We observed two new peptides at MH(+) = 973.7 and MH(+) = 1001.8 in the pepsin digestion of DSF-inhibited enzyme. These two peptides were subsequently subjected to HPLC-MS/MS for sequence determination. Both peptides possessed the sequence FNQGQC(301)C(302)C(303), derived from the enzyme active site region, and were modified at Cys(302) by N-ethylcarbamoyl (+71 Da) and N-diethylcarbamoyl (+99 Da) adducts. These findings indicated that N-dealkylation may be an important step in DSF metabolism, and that the inhibition of ALDH occurred by carbamoylation caused by one of the DSF metabolites, most likely S-methyl-N,N-diethylthiocarbamoyl sulfoxide (MeDTC-SO). Finally, there was no evidence of the presence of an intramolecule disulfide bridge modification on the peptide FNQGQCCC.

Alcohol Deterrents↗
PubMed1997

Inhibition of aldehyde dehydrogenase by disulfiram and its metabolite methyl diethylthiocarbamoyl-sulfoxide.

Disulfiram (DSF) is presently the only available drug used in the aversion therapy of recovering alcoholics. It acts by inhibiting aldehyde dehydrogenase (ALDH), leading to high blood levels of acetaldehyde. The in vitro inhibition of ALDH by DSF and its metabolites was systematically studied by combined enzyme inhibition assay with direct molecular weight determination of the same sample using electrospray ionization-mass spectrometry (ESI-MS). Enzyme activity was measured after incubating yeast ALDH (yALDH) with excess concentrations of DSF, methyl diethyldithiocarbamate (MeDDC) and methyl diethylthiocarbamoyl-sulfoxide (MeDTC-SO) and then subjected to analysis by ESI-MS. Addition of DSF resulted in complete enzyme inhibition; however, ESI-MS analysis demonstrated no discernible shift in molecular weight, indicating that no intermolecular adduct was formed with the protein. Treatment of yALDH with MeDTC-SO also completely abolished yALDH activity with a concomitant increase of + approximately 100 Da in the molecular mass of the enzyme. This indicated formation of a covalent carbamoyl protein adduct. Furthermore, the effects of dithiothreitol (DTT) were examined on samples of inhibited protein in vitro. At pH 7.5, DTT completely reversed inhibition after DSF treatment. yALDH inhibited by MeDTC-SO could not be recovered by DTT at pH 7.5, but at pH 9 the enzymic activity was fully restored and a mass loss of approximately 100 Da was noted. This observations are consistent with mechanisms where inhibition of yALDH by DSF in vitro involves oxidation of the active site, whereas MeDTC-SO forms a covalent adduct with the protein in vitro resulting in cessation of enzyme activity.

Aldehyde Dehydrogenase↗
PubMed1997

Inhibition of human mitochondrial aldehyde dehydrogenase by the disulfiram metabolite S-methyl-N,N-diethylthiocarbamoyl sulfoxide: structural characterization of the enzyme adduct by HPLC-tandem mass spectrometry.

S-Methyl-N,N-diethylthiocarbamoyl sulfoxide (MeDTC-SO) is a known metabolite of the aversion therapy drug disulfiram (DSF). MeDTC-SO is also a potent inhibitor of human mitochondrial aldehyde dehydrogenase (hmALDH) with an IC50 of 1.5 microM. Inhibition of the enzyme by MeDTC-SO resulted in the addition of approximately 100 Da to the molecular mass of the intact protein, as determined by on-line HPLC-electrospray ionization MS (LC-MS). Dialysis of the inhibited protein did not reverse the inhibition, and the molecular mass of 54,533 Da (+/- 0.01%) remained unchanged, indicating that a covalent modification of the protein had occurred. Proteolytic digestion of hmALDH under basic conditions using trypsin at pH 7.8 revealed that the adduct was base labile. However, treating the adducted protein with endopeptidase-Glu-C at pH 3.7 produced a peptide adduct at MH+ = 4924, tentatively attributable to a carbamoylated peptide. This peptide contains three adjacent cysteines, one of which has been implicated as a key amino acid in the highly conserved active site region of ALDH. A pepsin digestion of hmALDH carried out at pH 3.7 and subsequent LC-MS analysis revealed an ion at MH2(2+) = 501.5, corresponding to the carbamoylated peptide FNQGQC1C2C3. This peptide contains the same adjacent active site cysteines. This latter peptide was subjected to LC-MS/MS, which enabled us to determine that the site of carbamoylation was at Cys2. The MS/MS product ion data also confirmed the presence of a carbamoyl group as the adduct species.

Aldehyde Dehydrogenase↗
PubMed1997

Pretranslational and posttranslational regulation of rat hepatic CYPs 3A2 and 2E1 by disulfiram.

The aldehyde dehydrogenase inhibitor disulfiram (DS) has been used to deter drinking in alcoholics, but it also precipitates pharmacokinetic interactions with coadministered drugs. From previous experiments conducted in vitro, it has been proposed that the ethanol-inducible cytochrome P450 2E1 (CYP2E1) is the major target for inhibition by DS, but the inference from reported drug interactions is that the drug inhibits multiple CYPs. The aim of the present study was to evaluate the inhibition of major constitutive CYPs in rat liver by DS. Thus, the effects of DS on activities mediated by CYPs 2A1/2, 2C11, 2E1, and 3A, which constitute approximately 80% of total CYPs in male rat liver, were evaluated. It was found that CYP2E1-mediated aniline 4-hydroxylase activity was weakly inhibited by DS in vitro, but that preincubation of the drug with NADPH-supplemented microsomes to generate metabolites of DS enhanced the extent of inhibition somewhat. In contrast, constitutive testosterone hydroxylases were inhibited effectively at low concentrations of DS (20 microM decreased the activities of all hydroxylation pathways to 40-60% of control), and a preincubation step between DS and NADPH-fortified microsomes enhanced the inhibition of CYP2C11 and 3A2 activities. In vivo studies were undertaken in which a single dose of DS (100 mg/kg, i.p.) was administered to rats; 24 hr later, CYP2E1-mediated aniline 4-hydroxylase activity was decreased to about 50% of the activity in untreated control rats. CYP2E1 apoprotein and mRNA were also decreased to 38% of the respective control, and CYP3A apoprotein and CYP3A2 mRNA responded similarly. In contrast, CYP2C11 apoprotein was decreased to 66% of control after DS administration, and CYP2A1 expression was unchanged. These findings establish that multiple CYPs are targets for inhibition by DS and provide a basis for clinically significant drug interactions involving CYPs other than 2E1. In addition, the in vivo modulation of CYP function by DS administration is not restricted to enzyme inactivation and may also include down-regulatory effects mediated at a pretranslational level.

Alcohol Deterrents↗
PubMed2003

Disulfiram facilitates the development and expression of locomotor sensitization to cocaine in rats.

BACKGROUND: Disulfiram (DS; Antabuse) inhibits dopamine-beta-hydroxylase leading to increased brain dopamine levels and shows treatment efficacy for cocaine addiction. Yet few preclinical studies have been performed. This study establishes the effects of DS on locomotor sensitization to cocaine in rats. METHODS: Rats were administered vehicle, cocaine (10 mg/kg; intraperitoneally [IP]), or DS (50 or 100 mg/kg; IP) alone or in combination for 5 days (development phase). Locomotor activity was measured for 60-min each day. After a 10-day drug washout, rats were administered cocaine, and locomotor activity was measured (expression phase). Plasma cocaine levels were assessed in separate groups of rats administered one of two cocaine doses (0 or 10 mg/kg) and one of two DS doses (0 or 100 mg/kg) for 5 days. Ten days later, blood was collected 60-min postcocaine injection. RESULTS: The development of cocaine locomotor sensitization was facilitated by DS even though DS alone had minimal effect on activity levels. Furthermore, expression of sensitization was greatest in rats previously administered DS, an effect that cannot be attributed to altered plasma cocaine levels. CONCLUSIONS: Because DS shows treatment efficacy for cocaine addiction, results from this study suggest potential treatment agents should enhance, not attenuate, locomotor sensitization in rats.

Animals↗
PubMed2001

Overview--in vitro inhibition of aldehyde dehydrogenase by disulfiram and metabolites.

Disulfiram (DSF) has found extensive use in the aversion therapy treatment of recovering alcoholics. It is known that DSF or a metabolite irreversibly inhibits aldehyde dehydrogenase (ALDH). However, the actual mechanism of inhibition is still not known. In this work we describe the in vitro interactions of DSF, as well as a principal metabolite S-methyl-N,N-diethylthiocarbamoyl sulfoxide (MeDTC-SO), with both recombinant rat liver mitochondrial monomeric ALDH (rmALDH) and homotetrameric rmALDH. We show that DSF directly inhibits rmALDH (IC(50)=36.4 microM) by inducing the formation of an intramolecular disulfide bond. We also demonstrate by HPLC-MS analysis of a Glu-C digest of DSF-treated rmALDH that the intramolecular disulfide bridge formed involves two of the three cysteines located at the active site of the enzyme. Using a combination of HPLC-MS and HPLC-MS/MS, we further show that the electrophilic metabolite MeDTC-SO also inhibits rmALDH (IC(50)=4.62 microM). We isolate and identify a carbamoylated peptide at Cys(302) with the sequence FNQGQC(301)C(302)C(303). Hence we show that MeDTC-SO exhibits its inhibitory effect by covalently modifying the -SH side-chain of Cys(302), present at the active site rmALDH. Finally we show using SEC-MS that both DSF and MeDTC-SO do not prevent formation of the homotetramer of rmALDH, but inhibit the enzyme by acting directly at the active site of specific monomers of rmALDH.

Aldehyde Dehydrogenase↗