Inhibition of mitochondrial aldehyde dehydrogenase by malondialdehyde.
Rat liver mitochondria contain an aldehyde dehydrogenase (ALDH, EC 1.2.1.3) with a low Km for acetaldehyde (2 microM) which is susceptible to inhibition by a variety of agents including p-chloromercuribenzoate and arsenite. This low Km ALDH isozyme has been shown to be decreased in activity following CCl4 treatment in vivo and by lipid peroxidation in vitro. Malondialdehyde, the most studied product of lipid peroxidation, was investigated for possible inhibitory effects on the low Km ALDH for rat liver mitochondria. Malondialdehyde was found to be a potent inhibitor of the enzyme. The enzyme was equally sensitive to inhibition when intact mitochondrial preparations were compared with disrupted mitochondria. The extent of enzyme inhibition was dependent on malondialdehyde concentration and time of incubation. High concentrations of malondialdehyde completely inhibited low Km mitochondrial ALDH activity. Malondialdehyde was found to inhibit the low Km ALDH irreversibly. The rate of ALDH inactivation exhibited two phases, one a rapid rate phase (5-15 s) and a second slower rate phase, both of which showed rates which were dependent on malondialdehyde concentration. These data show that malondialdehyde is a potent, high affinity, irreversible inhibitor of the low Km ALDH of rat liver mitochondria. This ALDH isozyme is considered to be the most important enzyme in acetaldehyde metabolism. Malondialdehyde inhibition of the low Km ALDH may be important since both ethanol and acetaldehyde are thought to stimulate hepatic lipid peroxidation.
D000444:Aldehyde Dehydrogenase; D000445:Aldehyde Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D001151:Arsenic / Q000494:pharmacology; D018053:Arsenites; D002729:Chloromercuribenzoates / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008314:Malonates / Q000494:pharmacology*; D008315:Malondialdehyde / Q000494:pharmacology*; D008930:Mitochondria, Liver / Q000201:enzymology*; D051381:Rats; D011919:Rats, Inbred Strains; D020245:p-Chloromercuribenzoic Acid
D018053:Arsenites; D002729:Chloromercuribenzoates; D008314:Malonates; D008315:Malondialdehyde; D020245:p-Chloromercuribenzoic Acid; D000445:Aldehyde Oxidoreductases; D000444:Aldehyde Dehydrogenase; C015001:arsenite; D001151:Arsenic