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PubMedDate not supplied

Dependence of tyrosine and dopamine-beta-hydroxylases activities on disulfiram and diethyldithiocarbamate level in guinea pig brain and heart.

Tyrosine hydroxylase and dopamine-(DA)-beta-hydroxylase acitvities in guinea pig brain and heart were determined at various time after disulfiram (DS) and sodium diethyldithiocarbamate (DDC) injections. In the same tissues DS and DDC levels were measured. The linear relationship between the above enzymes activities and the levels of DDC in brain and heart has been found. The inactivation of the both enzymes is dependent on DDC content in tissues.

Animals↗
PubMed1989

Comparative effects of disulfiram and diethyldithiocarbamate on cadmium distribution in mice.

It has been reported that disulfiram (DSF) and diethyldithiocarbamate (DDTC) have similar actions on cadmium (Cd) distribution in maternal and fetal organs when given to pregnant mice prior to and again immediately after iv administration of Cd (Arch. Toxicol. 55, 161-167, 1984). We have now examined Cd distribution in mice in which virtually all of the Cd was bound to metallothionein (MT) in an attempt to simulate more closely the condition of low level, chronic Cd exposure. When DSF was incorporated into food and ingested by mice over a 4-hr period on each of four days, hepatic and pulmonary Cd levels were reduced significantly. When given ip at 500 mg/kg, DDTC lowered hepatic, renal, splenic, and pancreatic Cd levels, but increased Cd concentrations in brain, testes, heart, and lungs. When DSF was given at 500 mg/kg ip, it lowered hepatic, splenic, testicular, and pancreatic Cd levels, but increased Cd concentrations in heart and brain. In contrast to DDTC, DSF had no effect on pulmonary or renal Cd. When given as a bolus dose po for five days at 1.0 mmole/kg, DDTC lowered renal, splenic, testicular, and pancreatic Cd levels, but increased Cd concentrations in brain and heart. There was no effect on hepatic or pulmonary Cd. When given at the same dose po, DSF did not alter the Cd concentration of any organ assessed. We suggest that studies of interactions of various xenobiotics with Cd in vivo should be done with an animal model which simulates chronic Cd exposure rather than acute Cd intoxication.

Animals↗
PubMed1989

Potentiation of nitrogen mustard cytotoxicity by disulfiram, diethyldithiocarbamic acid, and diethylamine in mice.

Disulfiram (DSF) and its metabolites, diethyldithiocarbamic acid (DDC) and diethylamine (DEA), were studied as pretreatments in combination with the alkylating agent nitrogen mustard (HN2) on the cytotoxicity of HN2 against both leukemia cells and normal hematopoietic stem cells. Both time intervals and dose relationships were examined. DSF showed a substantial potentiation of HN2 cytotoxicity against murine AKR leukemia cell spleen colony-forming units (LCFU) when given i.p. between 15 to 30 min prior to HN2 i.v. treatment. For 3 mg DSF/mouse pretreatment, leukemia LCFU survival was about 10(-6) whereas it was about 10(-2) for HN2 alone. The extent of this potentiation decreased as the time between treatments increased. Significant potentiation was noted even when a low dose of DSF (0.25 mg/mouse) was administered 15 min before HN2. However, DSF had little if any effect on the modulation of HN2 cytotoxicity to normal hematopoietic cell spleen colony-forming units (NCFU). DDC showed an increasing potentiation of HN2 cytotoxicity against LCFU when given i.p. prior to HN2 i.v. treatment. The maximum effect was noted between 2 and 4 h with a surviving fraction for LCFU between 10(-5) and 10(-6) for 20 mg/mouse DDC pretreatment. The extent of this effect then decreased as the time interval increased beyond 4 h, but it was still significant for the 24-h interval. This pronounced potentiation effect was dose dependent for DDC. The compound exhibited a protective effect against HN2 cytotoxicity to NCFU when given 15 min before HN2. This protection decreased with increased time interval. DEA (20 mg/mouse) did not show a significant potentiation of HN2 cytotoxicity against LCFU when administered i.p. prior to HN2. Also, DEA did not show any significant protection of NCFU.

Animals↗
PubMed1989

Oxidation of diethyldithiocarbamate to disulfiram by liver microsomal cytochrome P-450-containing monooxygenase system.

We examined the involvement of cytochrome P-450 in the oxidation of diethyldithiocarbamate (DTC) to disulfiram (DS) by liver microsomes in the presence of NADPH. DS difference spectra of liver microsomes showed a peak and trough at about 385 and 418 nm, respectively, which disappeared after further addition of glutathione (GSH). DTC alone had little effect on the microsomal spectrum, however, the addition of NADPH gradually produced a spectral change having a trough at 416-417 nm, which waned upon further addition of GSH. Microsomal DS production was increased by phenobarbital pretreatment and decreased by carbon tetrachloride pretreatment, depending on the activity of the cytochrome P-450-monooxygenase system. With microsomes peroxidized by cumene hydroperoxide, the extent of NADPH-dependent DS production lowered in proportion to the decrease in cytochrome P-450. Inhibitors of cytochrome P-450 such as SKF-525A, metyrapone and n-octylamine dose-dependently inhibited the DS production. Sodium azide, an inhibitor of catalase, increased the DS production, whereas addition of exogenous catalase only slightly suppressed it. It is concluded that oxidation of DTC to DS by liver microsomes largely proceeds via the cytochrome P-450-containing monooxygenase system and partly by hydrogen peroxide generated during NADPH oxidation.

Animals↗
PubMed1988

Effects of carbon disulfide, diethyldithiocarbamate, and disulfiram on drug metabolism in the perfused rat liver.

The effects of carbon disulfide (CS2), diethyldithiocarbamate (DTC) and disulfiram (DS) on hepatic drug metabolism were studied in a noncirculating and hemoglobin-free rat liver perfusion system using p-nitroanisole (p-NA) as a substrate. Infusion of 1 mumol of CS2 into a normal rat liver instantaneously lowered the free p-nitrophenol (p-NP) concentration in the effluent perfusate; however, the effects on the levels of its glucuronide and sulfate conjugates were much less marked. The suppression of p-NP production by CS2 was also observed in livers isolated from phenobarbital (PB)- and 3-methylcholanthrene (3-MC)-treated rats; to a greater extent, in the normal and 3-MC groups. Partial recovery was observed in the normal and PB-treated groups, but it was slow and slight in the 3-MC-treated group. Infusion of DTC, up to 20 mumol, did not lower free p-NP levels, but a slight transient increase was noted, especially in the 3-MC-group. Using 50 mumol of DTC, a slight suppression resulted. DS, up to 20 mumol, did not decrease p-NP production, but rather gradually increased it, especially in the 3-MC-treated groups. Without the p-NP infusion, about 60-70% of the infused DS (10 mumol) was recovered in the effluent perfusate as DTC plus its glucuronide conjugate, the formation of the latter being greatly enhanced by the inducer treatments and markedly suppressed during the p-NP infusion. In this paper, these results are discussed with regards to the mechanisms of drug metabolism inhibition by DS administration.

Animals↗
PubMed1988

Oxidation of diethyldithiocarbamate to disulfiram by liver microsomes in the presence of NADPH and subsequent loss of microsomal enzyme activity in vitro.

Oxidation of diethyldithiocarbamate (DTC) to disulfiram (DS) by liver microsomes was tested in vitro by using a copper-DTC chelate formation reaction after the conversion of DS to DTC by glutathione (GSH). In the presence of NADPH, microsomes produced DS from DTC in both the free and microsome-bound forms, the former being greater than the latter. DS production was dependent on NADPH and DTC concentrations, and incubation time. Increases in microsomal concentrations, up to a certain level, also increased the free and total DS production. NADH was only somewhat effective, both the exposure to a nitrogen atmosphere and heat-denaturation of the microsomes suppressed the reaction. Preincubation of microsomes with both DTC and NADPH markedly decreased aniline hydroxylase, p-nitroanisole O-demethylase and glucose-6-phosphatase activities, and moderately decreased NADH-ferricyanide and NADH-cytochrome c reductase, but NADPH-cytochrome c reductase was minimally affected. DTC alone had only slight effects on the activities. DS also decreased these enzyme activities, particularly glucose-6-phosphatase; the loss of NADPH-cytochrome c reductase activity being protected in the presence of NADPH. GSH almost completely prevented the loss of microsomal enzyme activities induced by DTC and NADPH except for the drug metabolizing activities, in which protection was incomplete. The microsomal oxidation of DTC to DS could play a role in the action of DS in the liver, since DS is rapidly degradated to DTC in vivo.

Animals↗
PubMedDate not supplied

Effect of disulfiram pretreatment on the tissue distribution, macromolecular binding, and excretion of [U-1,2-14C]dichloroethane in the rat.

The effect of disulfiram (DSF) pretreatment on the distribution of [14C]ethylene dichloride (EDC) in selected organs and/or tissues of control and EDC-pretreated rats was studied. The presence of EDC metabolites and their binding to an acid-insoluble extract of the tissues, as well as purified protein and DNA, were evaluated. Dietary DSF was found to modulate the distribution, excretion, and macromolecular binding of EDC and/or its metabolites at 4 and 24 hr following ip administration. The urinary excretion of [14C]EDC metabolites was not affected by subchronic inhalation exposure to nonradiolabeled EDC. However, DSF pretreatment increased the fat deposition of EDC and decreased the urinary excretion of its metabolites. DSF also increased the binding of EDC metabolites to DNA and decreased the binding to protein in the liver, kidneys, spleen, and testes. However, prior exposure to EDC alone increased the binding of its metabolites to DNA in the kidneys only.

Animals↗
PubMed1985

Influence of disulfiram, diethyldithiocarbamate and carbon disulfide on the metabolic formation of trifluoroacetic acid from halothane in the rat.

Halothane (H), 2-bromo-2-chloro-1,1,1-trifluoroethane, was metabolized to trifluoroacetic acid (TFAA) over a very long time (several days) in rats after a 1 h exposure to the inhalational anesthetic. H inhibited its own metabolism as long as anesthetically active concentrations existed in the serum and tissue. That fraction of H which was not exhaled rapidly by the lung after the anesthesia was metabolized mainly over the time range from 5-48 h: 68% of the total amount of TFAA eliminated in the urine during 144 h (about 4 mg) were found in this time period. Disulfiram (D) dose dependently inhibited the formation of TFAA from H in vivo and in vitro, in liver microsomes of phenobarbital treated rats. Diethyldithiocarbamate (DDTC) and carbon disulfide (CS2), two metabolites of D, given to rats immediately after the H-anesthesia also reduced the metabolic formation of TFAA. However, if DDTC and CS2 were given 24 h before the anesthesia they caused only a small decrease in serum TFAA concentration. This finding indicates that both metabolites of D have only short-lasting inhibitory effects. In contrast, the inhibition of the oxidative metabolism of H by D seems to persist over a long time, since a small but significant decrease in the serum TFAA concentration was found even if D was given 72 h before the H-anesthesia. It was concluded that in vivo CS2 is really the active inhibitor. The short-lasting inhibitory effect of DDTC may be explained by its fast metabolic transformation into CS2, whereas the long-lasting effect of D is caused by its delayed degradation into this metabolite.

Anesthesia, Inhalation↗
PubMedDate not supplied

Effect of disulfiram on function of the liver of rats with galactosamine-induced hepatitis.

This study was aimed to examine whether disulfiram (DS) may exacerbate the pre-existing liver damage induced by D-galactosamine (GalN) in rats. DS, 600 mg/kg, administered by gavage for 3 days caused an increase in asparagine aminotransferase (AspAT) and alkaline phosphatase (AP) and a decrease in cholinesterase (ChE) activity in the serum and decrease in AspAT and ChE activity in the liver. DS given to rats with GAlN-induced liver injury caused significant increase in alanine aminotransferase (A1AT) and bilirubin level in serum in comparison with rats with GalN-damaged liver but without DS treatment. In summary, DS exacerbates a damage of the liver of rats. This study supported the clinical observations showing enhanced liver damage in alcoholics treated with DS.

Alanine Transaminase↗
PubMedDate not supplied

[Disulfiram and butylhydroxyanisole induction of glutathione-S- and UDP glucuronosyltransferase activities in the liver and its role in preventing the toxic action of diethylnitrosamine in rats].

Pretreatment of Wistar male rats with disulfiram (DSF, 500 mg/kg, three times, orally) or butylhydroxyanisole (BHA, 400 mg/kg, three times, orally) was shown to protect animals completely against intoxication with diethylnitrosamine (DENA) in the dose equal to LD50 (280 mg/kg, once, orally). DSF and BHA were also found to produce a significant modification of the 2nd stage of metabolism of xenobiotics: to induce the activity of cytosol and microsomal glutathione-S-transferases (GST) (by 1.7 and 2 times, 2.3 and 3.1 times, respectively), the content of glutathione (by 1.6 and 2.3 times), the activity of UDP glucuronosyltransferase (UDP-GT) (by 2 and 3.2 times) but to decrease the activity of sulfotransferase (by 22 and 35%). Administration of DENA decreased the activity of GST, UDP-GT and the content of glutathione, however they remain significantly higher than the corresponding parameters in intact animals. It is concluded that the protective action of DSF and BHA is related greatly to the induction of the systems of conjugation with glutathione and UDP-glucuronic acid.

Animals↗
PubMedDate not supplied

[Effect of disulfiram on the free amino acid pool of the brain tissue of rats].

Disulfiram (DS) (200 mg/kg for 3 days) decreases contents of GABA, phenylalanine, histidine, cystathionine, methionine, ornithine, leucine and lysine. The effect of DS is potentiated by ethanol (1 g/kg). In this case concentrations of alanine, valine, isoleucine and tyrosine additionally fall. Probable roles of GABA-ergic system and amino acids--precursors, neurotransmitters in the realization of therapeutic and, perhaps, side effects of DS are discussed. Additive effects of DS and its combination with ethanol indicates a significant contribution of acetaldehyde to the mentioned changes.

Acetaldehyde↗
PubMed1986

[Disulfiram-like reactions resulting from the administration of cephem antibiotics with methyltetrazolethiol moiety examined by using different doses].

The disulfiram-like reactions following the treatment of cephem antibiotics with methyltetrazolethiol moiety (latamoxef (LMOX) and cefoperazone (CPZ) was studied by using large (500 mg/kg) and small (50 mg/kg) doses of the drugs. Normal and fatty liver rats were injected intraperitoneally with the cephem antibiotics. After overnight fasting blood samples were obtained following an administration of 20% ethanol (2g/kg). Blood ethanol and acetaldehyde concentrations, and liver acetaldehyde dehydrogenase activity were determined. Blood ethanol concentration upon the small dose was similar to that obtained upon the large dose in both groups of normal and fatty liver rats. Blood acetaldehyde concentration upon the large dose was higher than that upon the small dose; 2-fold increase in normal rats and 2.6-4.7-fold increase in fatty liver rats were observed after administering LMOX, while 3.7-fold increase in normal rats and 5-5.7-fold increase in fatty liver rats upon administering CPZ. Additionally, liver acetaldehyde dehydrogenase activity (Enzyme 1) observed upon the large dose was lower than that observed upon the small dose; the degree of reduction was 33% in normal and 19% in fatty liver rats upon the administration of LMOX, while 37% in normal and 45% in fatty liver rats upon the administration of CPZ.

Acetaldehyde↗
PubMed1986

In vitro inhibition of microtubule assembly by disulfiram.

Disulfiram (Tetraethylthiuram disulfide, DSF) inhibits in vitro tubulin polymerization in a dose-dependent manner after a preliminary incubation time. Electron micrographs show that microtubules are shorter and less numerous. This inhibition may be correlated to blockade of protein SH groups. The linkage of DSF-tubulin hinders the vinca alkaloids-tubulin binding as shown using radioactive assay and microcalorimetric measurements. These results could be responsible for the occurrence of some side effects observed during the therapeutic use of this drug.

Animals↗
PubMed1978

Proton magnetic resonance spectroscopic determination of disulfiram: collaborative study.

A proton magnetic resonance spectroscopic method for determining disulfiram in the bulk drug product and in the formulated material was collaboratively studied. The method depends on the use of chloroform-d as a solvent and hexamethylcyclotrisiloxane as the internal standard. No interference from tablet excipients was observed. The method is rapid and specific. Eighteen laboratories analyzed duplicate samples of a bulk drug product, a 250 mg tablet composite, and a 500 mg tablet composite. The average per cent results and standard deviations were 99.7 +/- 1.4, 100.9 +/- 2.0, and 99.9 +/- 2.2, respectively.

Disulfiram↗
PubMed1982

[Cephem antibiotics and alcohol metabolism: (1) Disulfiram-like reaction resulting from intravenous administration of cephem antibiotics].

Fifty to 500 mg/kg doses of the cephem antibiotics were intravenously injected to male rats twice a day for 3 days. After the last injection, the rats were fasted for 17 hours and then orally administered 2 g/kg or 20% ethanol. The blood levels of ethanol and acetaldehyde (AcH) were determined by gas chromatography. Cefotiam, cefsulodin, and cefazolin did not affect the blood levels of ethanol and AcH as compared with those of the control. Cefmetazole, cefamandole, and cefoperazone did not change the blood ethanol level, but these antibiotics increased the blood AcH level dose-dependently. Cefamandole was especially able to sustain a high blood AcH level for over 8 hours. All of the antibodies which increased blood AcH levels contain the 1-methyl-1H tetrazole-5-thiol (TZ) group in their chemical structure. Intravenous injection of TZ caused a significant increase of the blood AcH level without influence on the blood ethanol level. 1-(2-Dimethyl-aminoethyl 1H-tetrazole-5-thiol (MTZ), the functional group which is contained in cefotiam, did not affect the blood levels of ethanol and AcH. These results suggested that the disulfiram-like reaction of cefmetazole, cefamandole, and cefoperazone results from an increase of the blood AcH level, and the 3-substituent group in in aminocephalosporanic acid, i.e., TZ, is an important factor for the reaction.

Acetaldehyde↗
PubMed1983

Rapid degradation of disulfiram by serum albumin.

Interaction of disulfiram (DSF, tetraethylthiuram disulfide) with human plasma and albumin was studied by high performance liquid chromatography. Incubation of DSF with plasma resulted in a rapid reduction of the parent drug into diethyldithiocarbamate (DDC). At initial stages of incubation about one half of DDC in the reaction mixture was bound to protein. On further incubation, concentration of protein-bound DDC exceeded the concentration of free DDC. Similar results were obtained when DSF was incubated with bovine serum albumin (BSA) indicating that albumin is the major component of human plasma involved in the reduction of DSF. These data have implications both for the laboratory assay of DSF in human plasma and for the therapeutic use of the drug. When assaying the drug in plasma or serum, DSF standards prepared in protein solution for calibration should take into account the distribution of DSF into the parent drug and its derivatives in a time and protein concentration dependent manner. In a clinical setting, patients with a low serum albumin concentration might require small doses of DSF to achieve an optimal therapeutic effect.

Disulfiram↗
PubMed1980

Disulfiram-like reaction associated with a parenteral cephalosporin.

A disulfiram-like reaction attributed to cefoperazone, an investigational cephalosporin, is reported. Cefoperazone (T-1551, Pfizer Pharmaceuticals, Inc.), a semisynthetic, parenteral cephalosporin undergoing clinical trials in the United States, was administered in single 1-, 2-, and 3-g doses to 12 healthy volunteers. The drug was administered as a 5% solution by constant infusion over a five-minute period, and one week was allowed between doses. Approximately 25 hours after receiving the 3-g dose, one subject experienced facial flushing after drinking 12 fluid ounces of beer. A second ingestion of 24 ounces of beer eight hours later produced facial flushing, tachycardia, diaphoresis, and pounding headache; the symptoms lasted 1.5-2 hours. A subsequent rechallenge with beer five hours later produced an identical reaction, but the symptoms subsided rapidly. Further rechallenge 60 hours after receiving the drug produced no ill effects. No such reaction appears to have been reported previously as being associated with the administration of a cephalosporin.

Adult↗