Human mitochondrial aldehyde dehydrogenase inhibition by diethyldithiocarbamic acid methanethiol mixed disulfide: a derivative of disulfiram.
A derivative and possible physiological metabolite of disulfiram, diethyldithiocarbamic acid methanethiol mixed disulfide, is shown here for the first time to inactivate the mitochondrial low-Km isozyme of human aldehyde dehydrogenase (EC 1.2.1.3). By comparing inactivating effects of diethyldithiocarbamic acid mixed disulfides with thiols of increasing chain length evidence is provided that steric hindrance is the reason for lack of inhibition of the mitochondrial enzyme by disulfiram in vitro. Since methanethiol is a normal metabolite [(1983) Annu. Rev. Biochem. 52, 187-222] the results also suggest a mechanism by which aldehyde dehydrogenase is inhibited by disulfiram and diethyldithiocarbamic acid in vivo.
MacKerell
A D
AD
Vallari
R C
RC
Pietruszko
R
R
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D004221:Disulfiram / Q000031:analogs & derivatives / Q000494:pharmacology*; D004050:Ditiocarb / Q000031:analogs & derivatives / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007700:Kinetics; D008930:Mitochondria, Liver / Q000201:enzymology*; D013329:Structure-Activity Relationship; D013859:Thiocarbamates / Q000494:pharmacology*
D007527:Isoenzymes; D013859:Thiocarbamates; C043893:diethyldithiocarbamic acid methanethiol; D004050:Ditiocarb; D000444:Aldehyde Dehydrogenase; D004221:Disulfiram