Diethylthiocarbamic acid methyl ester. A potent inhibitor of aldehyde dehydrogenase found in rats treated with disulfiram or diethyldithiocarbamic acid methyl ester.Biochem Pharmacol. 1989 Apr 01; 38(7):1053-9.BP
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.
