title: Diethylthiocarbamic acid methyl ester. A potent inhibitor of aldehyde dehydrogenase found in rats treated with disulfiram or diethyldithiocarbamic acid methyl ester.
abstract: 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.
authors.affiliation: Department of Clinical Chemistry, General Hospital, Malmö, Sweden.
authors.forename: B
authors.initials: B
authors.lastname: Johansson
authors.forename: E N
authors.initials: EN
authors.lastname: Petersen
authors.forename: E
authors.initials: E
authors.lastname: Arnold
mesh_terms: 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
chemical_list: D013859:Thiocarbamates; D000431:Ethanol; C016571:methyl diethyldithiocarbamate; D003577:Cytochrome P-450 Enzyme System; D004050:Ditiocarb; D006899:Mixed Function Oxygenases; D000444:Aldehyde Dehydrogenase; D004221:Disulfiram