The effect of some analogues of disulfiram on the aldehyde dehydrogenases of sheep liver

Tm, Kitson

doi:10.1042/bj1550445

Cited by 31 publications

(14 citation statements)

References 13 publications

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“…Studies comparing the sensitivities of sheep liver cytoplasmic and mitochondrial aldehyde dehydrogenases to disulfiram [18,41] have also given close similarity to the results of Eckfeldt et al [8] with horse liver enzymes and to those of Greenfield and Pietruszko [21] with human liver enzymes. Similar differences in the Michaelis constants for NAD' have been reported for sheep [I21 and horse [8] liver cytoplasmic and mitochondrial enzymes, and the cytoplasmic enzymes from these animals show close similarity in a number of other steady-state kinetic parameters [13].…”

Section: Comparison Of' Sheep Liver Aldehyde Dehydrogenases With Othesupporting

confidence: 57%

Purification and Properties of Sheep‐Liver Aldehyde Dehydrogenases

MacGibbon

Motion

Crow

et al. 1979

European Journal of Biochemistry

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1. Sheep liver cytoplasmic aldehyde dehydrogenase was purified to homogeneity to give a sample with a specific activity of 380 nmol NADH min-' mg-'.2. An amino acid analysis of the enzyme gave results similar to those reported for aldehyde dehydrogenases from other sources. The isoelectric point was at pH 5.25 and the enzyme contained no significant amounts of metal ions.3. On the binding of NADH to the enzyme there is a shift in absorption maximum of NADH to 5. Ellman's reagent reacted only slowly with the enzyme but in the presence of sodium dodecylsulphate complete reaction occurred within a few minutes to an extent corresponding to 36 thiol groupsienzyme.6. Molecular weights were determined for both cytoplasmic and mitochondrial aldehyde dehydrogenases and were 212000 ? 8000 and 205000 respectively. Each enzyme consisted of four subunits with molecular weight of 53000 7. Properties of the cytoplasmic and mitochondria1 aldehyde dehydrogenases from sheep liver were compared with other mammalian liver aldehyde dehydrogenases. 2000.

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Section: Comparison Of' Sheep Liver Aldehyde Dehydrogenases With Othesupporting

confidence: 57%

Purification and Properties of Sheep‐Liver Aldehyde Dehydrogenases

MacGibbon

Motion

Crow

et al. 1979

European Journal of Biochemistry

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“…Phase I1 metabolism involves not only formation of diethyldithiomethylcarbamate (Me-D I X ) , a reaction which is mediated by an S-methyltransferase (32,33), but also glucuronidation of DDC (34). All of the metabolites discussed were found to be inactive as in vitro inhibitors of various isozymes of ALDH (35,36).…”

Section: Absorption and Biotransformationmentioning

confidence: 99%

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

Johansson¹

1992

Acta Psychiatr Scand

320

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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“…Various liver aldehyde dehydrogenases have comparable sensitivity to inhibition by TETD and other disulphides, with an interesting differential sensitivity being apparent for the cytoplasmic and mitochondria1 enzymes in sheep liver (Graham, 1951;Kitson, 1975Kitson, , 1976). The extremely steep dose-response curve exhibited by trypanosomes in culture is probably related to the time-dependent irreversible inhibition of the threonine dehydrogenase ; a similar phenomenon for sheep liver aldehyde dehydrogenase has been described by Kitson (1975).…”

Section: Crossmentioning

confidence: 99%