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Disulfiram treatment of alcoholism.

PURPOSE: For 40 years, disulfiram has been the alcohol-aversive drug used most frequently by American physicians in the treatment of alcohol dependency disorders. We reviewed the clinical literature regarding the risks, benefits, indications, and efficacy of this controversial drug and summarized current knowledge of this therapy. CONCLUSIONS: Disulfiram will produce an aversive reaction with ethanol, usually at a dose between 250 mg/day and 500 mg/day, although some patients may not have an aversive reaction at this level. Cardiac, hepatic, and neurologic toxicity can also occur within this dosage range. If disulfiram is to be used, the patient must clearly understand the risks of drinking while taking the drug, and the physician and patient must agree about the need for continued clinical supervision and monitoring for efficacy and side effects. The physician must also recognize that disulfiram is only an adjunctive therapy and that continued support, supervision, and other therapeutic measures are required. Disulfiram is probably effective in reducing the frequency of alcohol consumption in the compliant patient over the short term (e.g., 6 months). Certain subgroups of patients, such as those who are older, those who are more socially stable, and those who are well-motivated, may experience a beneficial effect for longer periods. The drug may be most effective in reducing short-term alcohol consumption when the compliance of the patient is supervised, although consideration of this kind of therapy includes the practical problems of supervising the patient and concerns that the supervising person may be placed in a difficult position. Prescription of disulfiram without accompanying education, counseling, and concomitant alcoholism therapy is not beneficial. Disulfiram has no proven effect on the long-term outcome of alcoholism.

Alcoholism↗

Disulfiram may mediate erythrocyte hemolysis induced by diethyldithiocarbamate and 1,4-naphthoquinone-2-sulfonate.

The increase in 1,4-naphthoquinone-2-sulfonate (NQS)-induced hemolysis by the superoxide dismutase inhibitor diethyldithiocarbamate (DEDC) was formerly attributed to increased superoxide anion levels in the erythrocyte. Our results show that removal of DEDC after preincubation and prior to the addition of NQS did not produce a significant increase in hemolysis, which suggests that hemolysis is primarily caused by the reaction products of DEDC with NQS and not to the inactivation of superoxide dismutase. Disulfiram, the oxidized product of DEDC, was found to be the main product formed when excess DEDC was reacted with NQS. Oxygen uptake also occurred and hydrogen peroxide was formed. The latter caused the oxidation of DEDC to disulfiram as catalase prevented disulfiram formation. Disulfiram was found to readily hemolyze erythrocytes at low concentrations as well as to crosslink the proteins in the erythrocyte membrane. Furthermore, disulfiram-induced hemolysis was markedly enhanced in glutathione-depleted erythrocytes. Disulfiram was subsequently found to readily oxidize glutathione in red blood cells. When equimolar concentrations of DEDC and NQS were reacted, the major product formed was the diethyldithiocarbamate:1,4-naphthoquinone (DEDC:NQS) conjugate. However, the principal mediator of erythrocyte hemolysis when excess DEDC is reacted with 1,4-naphthoquinone-2-sulfonate is disulfiram, whose mode of action may be to modify membrane protein sulfhydryls.

Animals↗

Photolysis of sulfiram: a mechanism for its disulfiram-like reaction.

Sulfiram, a drug applied topically to treat scabies, produces effects similar to those of disulfiram after subsequent ingestion of ethanol. Disulfiram, used in aversion therapy in the treatment of alcoholism, inhibits hepatic aldehyde dehydrogenase (ALDH) causing an accumulation of acetaldehyde after ethanol ingestion. The increased tissue levels of acetaldehyde cause a spectrum of undesirable side-effects including flushing, nausea, vomiting, and tachycardia, which are referred to as the disulfiram reaction. Previous studies have shown that in vitro sulfiram is a very weak inhibitor of ALDH, but solutions of sulfiram markedly increase in potency with time. In the present study, fresh solutions of sulfiram were exposed to fluorescent room light under ambient conditions and analyzed at timed intervals by HPLC. At least eight products, including disulfiram, were formed in the light-exposed sulfiram solutions, but not in solutions kept in the dark. Structural characterization of two of the photolysis products was obtained by on-line microbore HPLC-mass spectrometry (mu LC-MS) and on-line microbore HPLC-tandem mass spectrometry (mu LC-MS/MS) using continuous flow-liquid secondary ion mass spectrometry (CF-LSIMS) as the primary ionization method. Sulfiram was converted to disulfiram at an initial rate of 0.7%/hr, and the formation of disulfiram correlated with the increase in ALDH inhibition in vitro. The results of this investigation show that while sulfiram is a weak inhibitor of ALDH in vitro, it is readily photoconverted to disulfiram, a very potent inhibitor of ALDH, which may explain the adverse reaction to ethanol after sulfiram therapy.

Aldehyde Dehydrogenase↗

The inhibition of lipid peroxidation by disulfiram prevents the killing of cultured hepatocytes by allyl alcohol, tert-butyl hydroperoxide, hydrogen peroxide and diethyl maleate.

Disulfiram is a potent antioxidant that prevented the peroxidation of microsomal phospholipids induced by ADP/Fe3+ at concentrations as low as 1 microM. However, disulfiram had a biphasic action when used to assess the role of lipid peroxidation in the killing of cultured hepatocytes by an acute oxidative stress. At a relatively low concentration (10 microM), the antioxidant activity of disulfiram predominated, and there was protection against the killing of the hepatocytes by allyl alcohol, tert-butyl hydroperoxide, hydrogen peroxide, and diethyl maleate. As the concentration of disulfiram was increased above 10 microM, the extent of protection progressively decreased. Thus, with higher concentrations of disulfiram, there was a second action whose consequence is to obscure the protective effect of the lower doses. With the agents studied, this additional and as yet undefined action of disulfiram leads to the killing of the hepatocytes by a mechanism that is unrelated to the peroxidation of lipids. This biphasic action of disulfiram must be appreciated in any attempt to use this compound to assess the role of lipid peroxidation in toxic cell injury.

1-Propanol↗

Interaction of human cytoplasmic aldehyde dehydrogenase E1 with disulfiram.

Two equivalents of symmetrically labeled [14C]-disulfiram (tetraethylthiuram disulfide, Antabuse) interact with human liver cytoplasmic aldehyde dehydrogenase (ALDH) E1 (E.C. 1.2.1.3) inhibiting ca. 90% of total catalytic activity. Inhibition occurs without labeling of the enzyme but is associated with disappearance of four SH groups per molecule of enzyme. Inhibition is reversible by treatment with 2-mercaptoethanol suggesting that disulfiram oxidizes vicinal enzyme SH groups to disulfides. The radioactivity from disulfiram is recovered as diethyldithiocarbamate. SDS gel electrophoresis indicates that vicinal SH groups involved in the interaction with disulfiram occur on the same subunits. This is also consistent with the fact that introduction of disulfide bonds by disulfiram is not accompanied by a major conformational change as evidenced by fluorescence polarization or circular dichroism. Experiments with o-iodosobenzoate suggest the presence of a third SH group in the vicinity of the two interacting with disulfiram. Inhibition of aldehyde dehydrogenase by disulfiram is not easily reversible by glutathione which might explain why new protein synthesis is required to regain enzyme activity in vivo.

Aldehyde Dehydrogenase↗

Combined lead acetate and disulfiram treatment-induced alterations of glial fibrillary acidic protein (GFA) immunoreactive astrocytes in brain smears.

Dithiocarbamates are known to form lipid-soluble complexes with lead and greatly increase brain lead levels. The present study was undertaken to investigate whether lead acetate, when administered together with disulfiram (Antabuse, metabolite of dithiocarbamate) during development, would induce morphological changes in brain astrocytes. Female Sprague-Dawley rats were given 0.25% lead acetate in the drinking water from day one of pregnancy and this treatment was continued after birth until the litters were 4 weeks old. In addition, some dams received disulfiram in a dose of 0.1 mmol/kg p.o. twice weekly and after parturition this dose was given s.c. directly to the offspring twice a week. Lead acetate and disulfiram treatments were discontinued at weaning and animals sacrificed 3 weeks later. Samples of parietal cortex, hippocampal formation and cerebellar cortex were dissected out and smeared onto glass-slides and astrocytes were visualized in toto using immunohistochemistry with antibodies against glial fibrillary acid protein (GFA), enabling morphometric analysis with a computerized image analyser. Animals treated with lead acetate showed a minor increase in the size of the GFA-immunoreactive astrocytes in parietal cortex smears, while animals treated with disulfiram showed no difference in size or form compared to controls. However, in combined lead acetate and disulfiram-treated animals a profound increase in astrocyte size and an increase in the number of processes of the individual GFA-immunoreactive astrocytes could be demonstrated in parietal cortex. No significant changes were noted in GFA-immunoreactive astrocytes of hippocampal smears following the different treatments, while GFA-immunoreactive astrocytes in cerebellar cortex smears were significantly smaller and had reduced number or processes following the combined lead acetate and disulfiram treatment compared to lead acetate treatment or controls. It is concluded that combined exposure to lead acetate and disulfiram during development induces regionally specific changes in GFA-immunoreactive astrocyte morphology. Furthermore, the present study demonstrates the usefulness of smear preparations combined with computerized image analysis to study the morphology of GFA-immunoreactive astrocytes as an index of toxic effects in CNS.

Animals↗

Inhibition of leukotriene B4 biosynthesis by disulfiram and A-64077 during carrageenan-induced pleurisy in the rat.

1. The effect of disulfiram and A-64077 on leukotriene B4 biosynthesis was investigated using human polymorphonuclear leukocyte preparations and an in vivo rat pleurisy assay. 2. Disulfiram inhibited the calcium ionophore-induced release of LTB4 by human leukocytes in vitro with an IC50 of 4.6 +/- 0.3 microM, a value similar to that observed with the 5-lipoxygenase inhibitor A-64077 (IC50 = 1.2 +/- 0.3 microM). These inhibitors were at least 100-fold more potent than diethyldithiocarbamate, the primary metabolite of disulfiram. 3. In a rat pleurisy model, the administration of A-64077 (p.o., 2 hr pretreatment) caused a marked decrease in LTB4 levels measureable after ionophore stimulation at doses of 3 and 10 mg kg (67 and 96% inhibition, respectively). Disulfiram was about a 100-fold less potent, inhibiting LTB4 release by 65% at 300 mg kg (p.o., 6 hr pretreatment). 4. In contrast to A-64077, the inhibitory effect of disulfiram on LTB4 production by isolated leukocytes from the pleural cavity was reduced by the addition of the cell-free pleural exudate, suggesting that protein binding or conversion of disulfiram to inactive species contributes to diminish the potency of the drug. 5. The results indicate that disulfiram, after oral administration in rats, causes an inhibition of leukotriene biosynthesis in the pleural cavity and further illustrate the limited specificity of this drug as an inhibitor of aldehyde dehydrogenase at doses generally used to inhibit this enzyme in vivo.

Aldehyde Dehydrogenase↗

Assessing disulfiram compliance: validational study of an abbreviated breath test procedure.

An abbreviated breath test for detecting the disulfiram metabolite carbon disulfide (CS2) was evaluated in an analogue investigation of the sensitivity of the test in identifying disulfiram and non-disulfiram intake in a group of 14 alcoholic inpatients. Disulfiram (250 mg) was administered within an ABAB repeated measures design over a 12-day period with corresponding breath tests administered during morning and afternoon time periods. Dependent measures included spectrophotometric analysis of reacted test samples and visual ratings of sample color. Results indicated that the test was highly sensitive in discriminating disulfiram administration for the group as a whole, as well as for individual subjects. Moreover, visual ratings were more accurate than spectrophotometric cut-off scores in identifying disulfiram administration. The test shows considerable promise as a rapid means of assessing disulfiram compliance.

Adult↗

S-methyl-N,N-diethylthiolcarbamate: a disulfiram metabolite and potent rat liver mitochondrial low Km aldehyde dehydrogenase inhibitor.

S-methyl-N,N-diethylthiolcarbamate-methyl ester (DETC-Me), a proposed disulfiram metabolite, was investigated both in vivo and in vitro for its effectiveness as a liver mitochondrial low Km aldehyde dehydrogenase (L Km ALDH) inhibitor. Male Sprague-Dawley rats were treated intraperitoneally with DETC-Me, killed at various times and L Km ALDH determined. DETC-Me was found to be a more potent in vivo inhibitor of L Km ALDH than either disulfiram, diethyldithiocarbamate (DDTC) or diethyldithiocarbamate-methyl ester (DDTC-Me). The ID50 for DETC-Me, DDTC-Me and disulfiram was 6.5, 15.5 and 56.2 mg/kg, respectively. The ID50 for DDTC was similar to DDTC-Me. Maximal inhibition of L Km ALDH occurred 30 minutes after DETC-Me administration. DETC-Me was ineffective as an in vitro inhibitor. DETC-Me produced a marked disulfiram-ethanol reaction (DER) at one-quarter of the dose of disulfiram or DDTC. Plasma DETC-Me in rats was greater after DETC-Me administration than after DDTC-Me, DDTC or disulfiram. In conclusion, DETC-Me is proposed to be a metabolite of disulfiram, and may be the immediate precursor of the chemical species responsible for L Km ALDH inhibition.

Aldehyde Dehydrogenase↗

Naltrexone and disulfiram in patients with alcohol dependence and comorbid post-traumatic stress disorder.

BACKGROUND: Although disulfiram and naltrexone have been approved by the Food and Drug Administration for the treatment of alcoholism, the effect of these medications on alcohol use outcomes and on psychiatric symptoms is still unknown in patients with co-occurring disorders post-traumatic stress disorder (PTSD). METHODS: Patients (n = 254) with a major Axis I psychiatric disorder and comorbid alcohol dependence were treated for 12 weeks in a medication study at three Veterans Administration outpatient clinics. Randomization included (1) open randomization to disulfiram or no disulfiram; and (2) double-blind randomization to naltrexone or placebo. This resulted in four groups: (1) naltrexone alone; (2) placebo alone; (3) disulfiram and naltrexone; or (4) disulfiram and placebo. Outcomes were measures of alcohol use, PTSD symptoms, alcohol craving, GGT levels and adverse events. RESULTS: 93 individuals (36.6%) met DSM-IV criteria for PTSD. Subjects with PTSD had better alcohol outcomes with active medication (naltrexone, disulfiram or the combination) than they did on placebo; overall psychiatric symptoms of PTSD improved. Individuals with PTSD were more likely to report some side effects when treated with the combination. CONCLUSIONS: The results of this study suggest that disulfiram and naltrexone are effective and safe for individuals with PTSD and comorbid alcohol dependence.

Adult↗

Increased lead concentration in brain and potentiation of lead-induced neuronal depression in rats after combined treatment with lead and disulfiram.

The effects of disulfiram (tetraethylthiuram disulfide) on blood and brain lead levels and on lead-induced changes in growth and cerebellar Purkinje neuron excitability were assessed in adult Sprague-Dawley rats. Disulfiram is metabolized to diethyldithiocarbamate, which forms a lipophilic complex with lead, and can thereby influence the tissue distribution of lead. Pregnant rats were exposed to 0.25% lead acetate or an equimolar amount of sodium acetate in the drinking water, and these treatments were continued for 4 weeks after birth. Half of the mothers from each group were given 0.1 mmole/kg disulfiram orally twice a week until parturition, after which the treatment was continued for 4 weeks in the respective pups in the form of subcutaneous injections. Although lead exposure markedly increased blood lead levels, the increase in brain lead levels was much more modest. Disulfiram markedly increased brain lead levels while blood lead levels in this group were only slightly elevated as compared to animals receiving lead alone. In addition, the lead + disulfiram group had depressed weight gain during maturation, and Purkinje neuron firing rates were reduced. The lead alone and disulfiram alone groups were not different from controls in these respects. These data suggest that disulfiram potentiates the adverse effects of lead on growth rates and on cerebellar Purkinje neuron function by facilitating the accumulation of lead in brain tissue.

Animals↗

Disulfiram causes sustained behavioral and biochemical effects in rats.

The present experiment examined effects of disulfiram (Antabuse) administration on behavioral measures of nociception (hot plate and tail flick), peripheral muscular performance (grip strength), motivated performance, balance, and coordination (rotorod) in 24 male Sprague-Dawley rats during and 2 wk after an eight-day administration of disulfiram. In addition, peptidylglycine 5(-hydroxylating monooxygenase (PHM) activity in several tissues and levels of alpha-amidated alpha-melanocyte stimulating hormone (alpha-MSH) in the neurointermediate lobe of the pituitary were assayed to evaluate biochemical effects of disulfiram. These particular assays were included because it has been reported that disulfiram affects alpha-amidated peptides via alteration of PHM activity. Decrements in all behavioral measures, except tail flick, occurred after one week of disulfiram administration. Decrements in grip strength continued for the 2 wk after cessation of disulfiram. Dose-related reductions in changes in PHM activity and levels of alpha-MSH were found 2 wk after cessation of disulfiram administration. The time course of the results suggest that changes in PHM activity may underlie decrements in grip strength. The present experiment provides a paradigm for further investigations of effects of alpha-amidated peptides on behavior.

Alcohol Deterrents↗

Toxicity of a treatment associating dopamine and disulfiram for catecholaminergic neuroblastoma SH-SY5Y cells: relationships with 3,4-dihydroxyphenylacetaldehyde formation.

3,4-Dihydroxyphenylacetaldehyde (DOPAL) is formed by the oxidative deamination of dopamine (DA) catalyzed by monoamine oxidases (MAO); then, the aldehyde is oxidized to 3,4-dihydroxyphenylacetic acid (DOPAC) by aldehyde dehydrogenases (ALDH) or reduced to 3,4-dihydroxyphenylethanol (DOPET) by aldose/aldehyde reductases. The present work aimed at evaluating the in vitro toxicity of DOPAL on catecholaminergic neuroblastoma SH-SY5Y cells which accumulate DA. DOPAL synthesis was stimulated by incubating cells with DA and blocking DOPAL oxidation by disulfiram, an irreversible inhibitor of ALDH. As evidenced by MTT reduction assays, DA and disulfiram treatments produced cell losses which increased with time. 10(-2)M DA reduced by 40% cell viability after a 1h treatment, when its TC(50) (concentration reducing viability by 50%) value was 7.3 x 10(-5) M after a 24 h treatment. For the same treatment periods, TC(50) values for disulfiram were 8 x 10(-5) and 8.7 x 10 (-7) M, respectively. MTT reduction assay performed after a 24h treatment followed by a 24h incubation in a drug-free medium evidenced that the toxicity of 10(-4)M DA or 10(-6)M disulfiram was potentiated by the second drug. HPLC measurements showed that DOPAL was produced at the early stages of the treatment by DA and disulfiram. This was evidenced by the significant increase in the ((DOPAL + DOPET)/DOPAC ratio observed after a combined 3h treatment by 10(-4)M DA and 10(-6)M disulfiram. Total contents in DA and DOPAL were greatly reduced at the end of a 15 h treatment, and disulfiram did not significantly enhanced the (DOPAL + DOPET)/DOPAC ratio. For both treatment durations, DOPAL and DOPET were detectable only in the extracellular medium. So, these results suggest that an early production of DOPAL could produce delayed toxic effects on SH-SY5Y cells. Production of DOPET and release of DOPAL could be important means for reducing DOPAL concentrations in dopaminergic neurons.

3,4-Dihydroxyphenylacetic Acid↗

Disulfiram-induced hepatitis. Report of four cases and review of the literature.

Liver test abnormalities following disulfiram therapy are common. However, overt disulfiram-induced hepatitis is rare but has a high mortality rate, specially when the etiologic role of disulfiram is not suspected and treatment is not discontinued. We report four cases of disulfiram-induced acute hepatitis with different degrees of severity and review the cases reported in the literature. The clinical spectrum of disulfiram hepatotoxicity ranges from minor elevation of serum aminotransferases to fulminant hepatitis. Although some patients with disulfiram-induced hepatitis have manifestations of hypersensitivity, recent clinical and experimental data suggest that disulfiram hepatotoxicity is produced by the accumulation of toxic metabolites.

Adult↗

Concordance between trifluoroacetic acid and hepatic protein trifluoroacetylation after disulfiram inhibition of halothane metabolism in rats.

BACKGROUND: Cytochrome P4502E1(CYP2E1)-mediated oxidation of halothane to a reactive intermediate (trifluoroacyl chloride) that covalently binds to hepatic proteins forming trifluoroacetylated neoantigens is believed to be the initiating event in a complex immunologic cascade culminating in antibody formation and severe hepatic necrosis ('halothane hepatitis') in susceptible patients. Trifluoroacyl chloride may also hydrolyze to the stable metabolite trifluoroacetic acid (TFA). CYP2E1 inactivation by disulfiram or its primary metabolite, diethyldithiocarbamate, inhibits human halothane oxidation to TFA in vitro and in vivo. Nevertheless, disulfiram effects on hepatic protein trifluoroacetylation by halothane in vivo are unknown. This investigation tested the hypotheses that disulfiram prevents halothane-dependent protein trifluoroacetylation in vivo, and that TFA represents a biomarker for hepatic protein trifluoroacetylation. METHODS: Rats were pretreated with isoniazid (CYP2E1 induction), isoniazid followed by disulfiram (CYP2E1 inhibition), or nothing (controls), then anesthetized with halothane or nothing (controls). Plasma and urine TFA were quantified by ion HPLC; hepatic microsomal TFA-proteins were analyzed by Western blot. RESULTS: CYP2E1 induction increased both TFA and TFA-protein formation compared with uninduced halothane-treated rats. Disulfiram, even after CYP2E1 induction, nearly abolished both TFA and TFA-protein formation. Pretreatments similarly affected both TFA and TFA-protein formation across all groups. CONCLUSIONS: Disulfiram inhibition of CYP2E1-mediated halothane oxidation prevents hepatic protein trifluoroacetylation. Based on the concordance between TFA and TFA-protein formation, TFA appears to be a valid biomarker for TFA-protein formation. Disulfiram inhibition of human halothane oxidation in vivo, previously assessed by diminished TFA formation, probably also confers inhibition of hepatic TFA-protein formation.

Anesthetics, Inhalation↗

Disulfiram and erythrocyte aldehyde dehydrogenase inhibition.

During disulfiram therapy erythrocyte aldehyde dehydrogenase (ALDH) was fully inhibited. The time for total loss of erythrocyte ALDH activity ranged from 36 to 120 hr. In contrast to the 85% recovery of in vitro disulfiram-inhibited ALDH activity, this in vivo disulfiram-ALDH inhibition could not be reversed by mercaptoethanol. It is proposed that the in vivo and in vitro mechanisms of ALDH inhibition by disulfiram differ. Erythrocyte ALDH activity can be readily monitored to determine patient compliance and is an accessible model for investigations of in vivo mechanisms of drug inhibition. Because the disulfiram-inhibited erythrocyte ALDH is not regenerated until new erythrocytes are made (120 days), a significant portion of the extrahepatic acetaldehyde metabolic capacity remains inhibited for long periods after disulfiram is discontinued. Thus, the recidivistic patient who discontinues disulfiram and waits several days (to regenerate liver ALDH activity) before drinking will be exposed to even higher ethanol-derived blood acetaldehyde levels than usual, which may induce further alcohol-associated organ damage and alcohol dependence.

Adult↗

The effect of disulfiram on the aldehyde dehydrogenases of sheep liver.

1. The effect of disulfiram on the activity of the cytoplasmic and mitochondrial aldehyde dehydrogenases of sheep liver was studied. 2. Disulfiram causes an immediate inhibition of the enzyme reaction. The effect on the cytoplasmic enzyme is much greater than on the mitochondrial enzyme. 3. In both cases, the initial partial inhibition is followed by a gradual irreversible loss of activity. 4. The pH-rate profile of the inactivation of the mitochondrial enzyme by disulfiram and the pH-dependence of the maximum velocity of the enzyme-catalysed reaction are both consistent with the involvement of a thiol group. 5. Excess of 2-mercaptoethanol or GSH abolishes the effect of disulfiram. However, equimolar amounts of either of these reagents and disulfiram cause an effect greater than does disulfiram alone. It was shown that the mixed disulphide, Et2N-CS-SS-CH2-CH2OH, strongly inhibits aldehyde dehydrogenase. 6. The inhibitory effect of diethyldithiocarbamate in vitro is due mainly to contamination by disulfiram.

Aldehyde Oxidoreductases↗

Studies on the interaction between disulfiram and sheep liver cytoplasmic aldehyde dehydrogenase.

The effect of disulfiram, [1-14C]disulfiram and some other thiol reagents on the activity of cytoplasmic aldehyde dehydrogenase from sheep liver was studied. The results are consistent with a rapid covalent interaction between disulfiram and the enzyme, and inconsistent with the notion that disulfiram is a reversible competitive inhibitor of cytoplasmic aldehyde dehydrogenase. There is a non-linear relationship between loss of about 90% of the enzyme activity and amount of disulfiram added; possible reasons for this are discussed. The remaining approx. 10% of activity is relatively insensitive to disulfiram. It is found that modification of only a small number of groups (one to two) per tetrameric enzyme molecule is responsible for the observed loss of activity. The dehydrogenase activity of the enzyme is affected more severely by disulfiram than is the esterase activity. Negatively charged thiol reagents have little or no effect on cytoplasmic aldehyde dehydrogenase. 2,2'-Dithiodipyridine is an activator of the enzyme.

Aldehyde Oxidoreductases↗