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

Hart, Bruce W.; Yourick, Jeffrey J.; Faiman, Morris D.

doi:10.1016/0741-8329(90)90079-r

Cited by 29 publications

(13 citation statements)

References 17 publications

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“…Other studies, however, reported Me-DTC to be inadequate as an in vitro inhibitor of ALDH 1 (38). Studies on isolated rat liver mitochondria showed ALDH 1 to be inhibited in vitro to only 25 '70 of its normal activity (39), which in fact agrees with results obtained on partly purified enzyme from bovine liver (68). Confusion between ALDH 1 and ALDH 2 led to rejection of Me-DTC as a possible in vivo inhibitor of mitochondria1 ALDH 1, yet this study was performed on cytosolic ALDH 2 (69).…”

Section: Inhibition Of Aldehyde Dehydrogenasessupporting

confidence: 85%

“…A previously unknown metabolite of DSF was found to be formed by oxidative desulphuration in rats treated with Me-DDC or DSF and in man on DSF treatment. The compound was identified as diethylthiomethylcarbamate (Me-DTC) (37,38,39). The oxidative reaction, which is mediated by microsomal P 450 mono-oxygenases, probably involves two additional oxidative steps.…”

Section: Absorption and Biotransformationmentioning

confidence: 99%

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

Johansson¹

1992

Acta Psychiatr Scand

324

272

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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 glutatione, 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. A large variety of solvents, drugs, pesticides and secondary metabolites of mushrooms interact with DSF in different ways. Organic solvents, mushrooms and several drugs sensitize humans to alcohol in a similar way as DSF, but usually with a less pronounced physiological response. However, more important is the metabolic interaction between DSF and drugs which utilize the same metabolic pathways. As a consequence of e...

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Section: Inhibition Of Aldehyde Dehydrogenasessupporting

confidence: 85%

Section: Absorption and Biotransformationmentioning

confidence: 99%

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

Johansson¹

1992

Acta Psychiatr Scand

324

272

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“…Me-DTC is considered to be most powerful irreversible inhibitor of aldehyde dehydrogenase. [6] If ethanol is ingested while taking disulfiram, the inhibition of aldehyde dehydrogenase causes increased levels of acetaldehyde; this results in a toxic reaction, commonly known as disulfiram-ethanol reaction (DER). Symptoms include throbbing headache, flushing, dizziness, nausea, vomiting, blurred vision, hypotension, tachycardia and hyperventilation.…”

Section: Disulfirammentioning

confidence: 99%

Pharmacoprophylaxis of alcohol dependence: Review and update Part I: Pharmacology

Grover

Bhateja

Basu

2007

Indian J Psychiatry

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Alcohol dependence is a major problem in India. The pharmacological armamentarium for relapse prevention of alcohol has widened with the addition of new drugs. In this article, we review the pharmacology and efficacy of the four most important such drugs: disulfiram, naltrexone, acamprosate and topiramate. The first part of this two-part review series concerns the comparative pharmacology and the second part concerns the efficacy studies. Overall, all four of these drugs have modest but clinically significant usefulness as pharmacoprophylactic agents for relapse prevention or minimization of alcohol dependence. Combinations might be helpful, especially for naltrexone and acamprosate. The issue of supervision and compliance remains important, especially for such drugs as disulfiram and naltrexone. Topiramate is a promising new agent and requires further study. Disulfiram, while very effective in compliant patients, presents challenges in terms of patient selection and side effects. For patients with hepatic impairment, acamprosate is a good choice.

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“…Human liver microsomes were also purchased from XenoTech (Kansas City, KS). MeDDC (Faiman et al, 1983), MeDDC sulfine (Mays et al, 1998), MeDDC sulfoxide (Mays et al, 1998, and MeDTC (Hart et al, 1990) were synthesized as previously described.…”

Section: Reagentsmentioning

confidence: 99%

Roles of FMO and CYP450 in the Metabolism in Human Liver Microsomes of S‐Methyl‐N, N‐Diethyldithiocarbamate, a Disulfiram Metabolite

Pike

Martin

Mays

et al. 1999

Alcoholism Clin & Exp Res

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

Cited by 29 publications

References 17 publications

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

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

Pharmacoprophylaxis of alcohol dependence: Review and update Part I: Pharmacology

Roles of FMO and CYP450 in the Metabolism in Human Liver Microsomes of S‐Methyl‐N, N‐Diethyldithiocarbamate, a Disulfiram Metabolite

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