Time course of the carbon tetrachloride-induced decrease in mitochondrial aldehyde dehydrogenase activity

Abstract

Hepatic microsomal enzymes like cytochrome P-450 and glucose 6-phosphatase are inhibited after exposure to CCl 4 in vivo. Since comparatively less is known about the effects of CCl 4 on nonmicrosomal enzymes, we investigated the rapidity by which CCl 4 inhibits the low K m mitochondrial aldehyde dehydrogenase (ALDH) isozyme, an enzyme known to be inhibited 24 hr after CCl 4 treatment. The activity of this ALDH isozyme was significantly lowered 6 and 12 hr after a single 1 ml/kg intragastric dose of CCl 4. The mitochondrial low K m ALDH specific activites exhibited a similar pattern of destruction/inhibition to the documented target enzyme microsomal cytochrome P-450 in that lowest values were observed 6 hr after CCl 4. These values were 44 and 37% of control for cytochrome P-450 content and the low K m ALDH activity, respectively. Alcohol dehydrogenase activity, expressed as activity per gram liver, was depressed 12 hr after CCl 4 dosing. Finally, the activity of the low K m cytosolic ALDH, the isozyme that metabolizes malondialdehyde at low concentrations, was not affected by CCl 4 treatment. The CCl 4-induced decline in the activity of the matrix ALDH isozyme occurs earlier than previously reported mitochondrial damage. The study of sensitive enzymes like the low K m ALDH may provide valuable information by which it may be possible to determine the relationship of the truly rapid biochemical effects of CCl 4 such as microsomal lipid peroxidation with later effects on nonmicrosomal components.