Inhibition of human erythrocyte and leukocyte aldehyde dehydrogenase activities by diethylthiocarbamic acid methyl ester. An in vivo metabolite of disulfiram.
The inhibitory effects of diethylthiocarbamic acid methyl ester (DTC-Me), an in vivo metabolite of disulfiram (Antabuse), on the aldehyde dehydrogenase (ALDH; EC 1.2.1.3) activities in human erythrocytes and leukocytes were studied. ALDH assays were performed by incubating intact isolated blood cells in the presence of different concentrations of DTC-Me, using 3,4-dihydroxy-phenylacetaldehyde, the aldehyde derived from dopamine, as the substrate. DTC-Me was more selective as inhibitor of the leukocyte ALDH activity (which resembles the liver "mitochondrial" low Km ALDH), whereas both disulfiram and diethyldithiocarbamic acid, the reduced monomer of disulfiram, were more selective for the erythrocyte ALDH (which is similar to the "cytosolic" high-Km ALDH). Diethylthiocarbamic acid, the free acid of DTC-Me, was less potent than DTC-Me, and caused similar inactivation of the erythrocyte and leukocyte ALDH activities. The inhibition of ALDH by DTC-Me could not be completely restored by extensive dilution of intact or sonicated blood cell samples, which indicated that ALDH was irreversibly inhibited. Since the inhibition patterns with DTC-Me agrees with the previously reported patterns of inhibition of the high-Km and low-Km isozymes after the administration of disulfiram, the results suggest that DTC-Me might be the active in vivo inhibitory metabolite of disulfiram.
Helander
A
A
Department of Zoophysiology, Uppsala University, Sweden.
Johansson
B
B
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000097:blood*; D004221:Disulfiram / Q000031:analogs & derivatives / Q000494:pharmacology; D004050:Ditiocarb / Q000031:analogs & derivatives*; D004912:Erythrocytes / Q000201:enzymology*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D007962:Leukocytes / Q000201:enzymology*; D013329:Structure-Activity Relationship; D013859:Thiocarbamates / Q000494:pharmacology*
D013859:Thiocarbamates; C016571:methyl diethyldithiocarbamate; D004050:Ditiocarb; D000444:Aldehyde Dehydrogenase; D004221:Disulfiram