Studies on the cyanamide-ethanol interaction. Dimethylcyanamide as an inhibitor of aldehyde dehydrogenase in vivo.
Administration of dimethylcyanamide (DMC) to rats caused a marked elevation in ethanol-derived blood acetaldehyde (AcH) and depressed the specific activity of the low Km mitochondrial aldehyde dehydrogenase (AIDH) by 90% at 12-24 hr, coincident with depletion of hepatic glutathione levels. Comparison of the relative efficacy of DMC and cyanamide in elevating blood AcH measured at 2 hr and 1 hr post-drug treatment, respectively, indicated that DMC was at least one-fifth as active as cyanamide. However, since the comparison was not made at optimal times for DMC (12-24 hr), it is likely that its activity in vivo approaches that of cyanamide itself. DMC was essentially inactive in vitro as an inhibitor of the low Km AIDH isozyme in intact rat liver mitochondria. Although methylcyanamide, the product of N-demethylation of DMC, was too unstable to be prepared for this evaluation, the higher monoalkyl cyanamide, n-propylcyanamide, was synthesized chemically and was shown to be a good inhibitor of the mitochondrial enzyme in vitro. These results suggest that DMC must be N-demethylated before being converted to a reactive species that inhibits AIDH activity.
D000444:Aldehyde Dehydrogenase; D000445:Aldehyde Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D003484:Cyanamide / Q000031:analogs & derivatives / Q000494:pharmacology*; D003486:Cyanides / Q000494:pharmacology*; D000431:Ethanol / Q000097:blood*; D005978:Glutathione / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008930:Mitochondria, Liver / Q000201:enzymology; D010101:Oxygen Consumption / Q000187:drug effects; D011335:Proadifen; D051381:Rats; D011919:Rats, Inbred Strains
D003486:Cyanides; C011787:dimethylcyanamide; D000431:Ethanol; D003484:Cyanamide; D011335:Proadifen; D000445:Aldehyde Oxidoreductases; D000444:Aldehyde Dehydrogenase; D005978:Glutathione