ROLE OF ALDEHYDE METABOLIZING ENZYMES IN MEDIATING EFFECTS OF ALDEHYDE PRODUCTS OF LIPID-PEROXIDATION IN LIVER-CELLS

It is well established that many types of tumor cells have reduced lip id peroxidation capacity compared to their normal counterparts. Change s in the activity of enzymes metabolizing aldehydes produced by lipid peroxidation have also been reported in a variety of tumor cells. We h ave investigated the relationship between changes in lipid peroxidatio n and changes in aldehyde-metabolizing enzymes in normal hepatocytes a nd two representative rat hepatoma cell lines, McA-RH-7777 and JM2. Co mpared to hepatocytes, both 7777 and JM2 cells have significantly lowe r basal and prooxidant-induced levels of lipid peroxidation than norma l hepatocytes. Using 4-hydroxynonenal (4-HNE) as substrate, both cell lines also have significantly reduced activities of alcohol dehydrogen ase (ADH) and glutathione S-transferase (GST) compared to hepatocytes. JM2 cells have significantly increased aldehyde dehydrogenase (ALDH) and aldehyde reductase (ALRD) activities with 4-HNE. In 7777 cells the ALDH and ALRD activities are not different from hepatocytes. The chan ges in enzyme activity are inversely correlated with the sensitivity o f cells to 4-HNE. JM2 cells, ,vith increased ALDH and ALRD and decreas ed ADH and GST, are much more resistant to the toxic effects of 4-HNE than 7777 cells. Normal hepatocytes and JM2 cells are approximately eq ually resistant to 4-HNE even though hepatocytes rely primarily on GST -mediated aldehyde conjugation to metabolize 4-HNE. Coupled with previ ous results from our laboratories, the overall increased sensitivity o f certain hepatoma cells to lipid aldehydes appears due to decreased a bility of these hepatoma cells to remove toxic products of lipid perox idation. Moreover, hepatoma cells with increased levels of aldehyde de hydrogenase and aldehyde reductase appear most like hepatocytes in the ir ability to metabolize lipid aldehydes.