Effects of disulfiram and its reduced metabolite, diethyl-dithiocarbamate on aldehyde dehydrogenase of human erythrocytes

Effects of Disulfiram, Cyanamide and 1‐Aminocyclopropanol on the Aldehyde Dehydrogenase Activity in Human Erythrocytes and Leukocytes

“…A much less pronounced inhibition was obtained in incubations with DDC as compared to disulfiram, which is in agreement with previous in vitro observations (Kitson 1976;Inoue et al 1982). Upon absorption into the blood-stream, disulfiram is rapidly and completely reduced by glutathione to two molecules of DDC, which is subsequently degraded to some other metabolites (Cobby et al 1977;Agarwal et al 1986), and no detectable amounts of unchanged drug could be found even in blood samples analysed within 5 min.…”

“…after the addition of disulfiram (Johansson 1986). DDC has, however, been found to be an equally potent ALDH inhibitor as disulfiram when administered in vivo to rats (Deitrich & Erwin 1971), and it has been suggested that DDC needs to be re-oxidized to disulfiram, or possibly co-oxidized with some natural metabolite to give a mixed disulfide (MacKerell et al 1985), in order to be a potent inactivator of ALDH (Deitrich & Erwin 1971;Inoue et al 1982;Kitson 1983). This is probably the cause of the slow onset and long duration of action of ALDH inhibition by disulfiram in vivo.…”

“…However, since the leukocyte/erythrocyte ratio in blood normally is about 1/800, the total activity in whole blood is practically all (98-99%) due to the erythrocyte activity (Helander & Tottmar 1986). With respect to biochemical characteristics, the erythrocyte ALDH is very similar to the liver "cytosolic" isozyme (ALDH 11; high-K, for acetaldehyde as substrate) (Helander & Tottmar 1986;Agarwal et al 1987), and is strongly affected by disulfiram (Inoue et al 1982;Towell et ul. 1983;Helander & Tottmar 1987b).…”

Disulfide interchange reactions: An enzymic case study

“…It was reasoned that both these reagents would label the enzyme with the -S-Me group, since in both cases the other moiety involved (diethyldithiocarbamate and the anion of 2thiopyridone, respectively) is a much better leaving group than the methanethiolate ion. The reactions involved are simply versions of eq 1: Enz -S-+ Et2NCS-S-S-Me--Enz-S-S-Me + Et2NCS2 (13) The synthesis that was used for these reagents is itself another example of the disulfide interchange reaction, utilizing the commercially available methyl methanethiosulfonate (10):…”

“…It seems therefore that in the liver there must be, at least to some extent, reoxidation of diethyldithiocarbamate to disulfiram in order for inactivation of the enzyme to occur. Several agents have been reported to be capable of bringing about this oxidation, such as cytochrome c, methaemoglobin, xanthine oxidase, and catalase (13). Experiments in vitro have shown that AldDH competes well against excess glutathione for low concentrations of disulfiram (14) [that is, reaction 9 is much faster than reaction 16] and presumably a similar situation applies in vivo even though the concentration of glutathione is as high as 5mM.…”