Inhibition of rat liver aldehyde dehydrogenase by carbon tetrachloride.
Current data suggests that aldehydic products of lipid peroxidation possess substantial cytotoxic properties. Carbon tetrachloride (CCl4), a potent stimulator of hepatic lipid peroxidation, was tested for possible effects on hepatocellular aldehyde metabolism. CCl4 (1 ml/kg) produced an elevation in serum alanine aminotransferase activity, hepatic fatty infiltration, centrilobular necrosis and significant decreases in the content of hepatic microsomal cytochrome P-450. Concurrently, the aldehyde dehydrogenase (E.C. 1.2.1.3) activity of mitochondrial and cytosolic fractions was significantly depressed. The lower Km aldehyde dehydrogenase located in the mitochondria showed the largest degree of inhibition (46%). An in vitro system which contained the low Km mitochondrial aldehyde dehydrogenase was employed to determine the role of microsomal lipid peroxidation in the inhibition of the enzyme. Aldehyde dehydrogenase was shown to be extremely sensitive to inhibition under conditions of NADPH or NADPH and CCl4-stimulated lipid peroxidation. Reduced glutathione (6 mM) provided complete protection of aldehyde dehydrogenase activity under conditions of NADPH-stimulated lipid peroxidation but could not protect activity loss during CCl4-stimulated microsomal lipid peroxidation. The degree of enzyme activity loss related well with the amount of thiobarbituric reacting substances present in the incubation mixture. These findings show that CCl4 decreases the activity of the aldehyde oxidizing enzyme, aldehyde dehydrogenase. This effect may accentuate cytotoxic effects of reactive aldehydic products generated during lipid peroxidation.
D000444:Aldehyde Dehydrogenase; D000445:Aldehyde Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002251:Carbon Tetrachloride / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D008054:Lipid Peroxides / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D009249:NADP / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013347:Subcellular Fractions / Q000187:drug effects / Q000201:enzymology
D008054:Lipid Peroxides; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D002251:Carbon Tetrachloride; D000445:Aldehyde Oxidoreductases; D000444:Aldehyde Dehydrogenase