Diethylthiocarbamic acid methyl ester. A potent inhibitor of aldehyde dehydrogenase found in rats treated with disulfiram or diethyldithiocarbamic acid methyl ester.
Rats were treated with disulfiram (Antabuse, DSF) or its metabolite diethyldithiocarbamic acid methyl ester (Me-DDC) and challenged with ethanol. The blood pressure response to ethanol was followed and blood was analyzed for DSF, Me-DDC and diethyldithiocarbamic acid (DDC). The rat liver aldehyde dehydrogenase (ALDH) isozyme activities were measured 2 hr after the ethanol challenge. Both treatments produced a significant fall in the blood pressure when challenged with ethanol, probably caused by a marked decrease in hepatocyte low Km and high Km activities. The mean plasma concentration ranges of Me-DDC and DDC were found to be 49-1241 nmol/l and 182-841 nmol/l, respectively, whereas DSF was undetectable. In addition, it was found that inactivation of hepatocyte low Km ALDH activity was dependent on preoxidation of Me-DDC by the microsomal cytochrome P-450 mixed function oxidases. Me-DDC was found to be oxidized under aerobic conditions in the presence of NADP to form diethylthiocarbamic acid methyl ester (Me-DTC). The structure was confirmed from its MS/EI fragmentation spectrum. Me-DTC was found to be a potent inhibitor of low Km ALDH when added to rat liver homogenate. The compound was also identified as a metabolite in rat blood collected from the DSF and Me-DDC treated rats, and in blood from human alcoholics on DSF treatment. Me-DTC appears to be more selective for the low Km isozymes whereas the opposite seems to be the case for the hydrolytic product, DTC.
Johansson
B
B
Department of Clinical Chemistry, General Hospital, Malmö, Sweden.
Petersen
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EN
Arnold
E
E
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004221:Disulfiram / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D004050:Ditiocarb / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D000431:Ethanol / Q000097:blood / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013859:Thiocarbamates / Q000096:biosynthesis* / Q000097:blood / Q000494:pharmacology
D013859:Thiocarbamates; D000431:Ethanol; C016571:methyl diethyldithiocarbamate; D003577:Cytochrome P-450 Enzyme System; D004050:Ditiocarb; D006899:Mixed Function Oxygenases; D000444:Aldehyde Dehydrogenase; D004221:Disulfiram