EFFECTS OF CLOFIBRIC AND BECLOBRIC ACID IN RAT AND MONKEY HEPATOCYTE PRIMARY CULTURE - INFLUENCE ON PEROXISOMAL AND MITOCHONDRIAL BETA-OXIDATION AND THE ACTIVITY OF CATALASE, GLUTATHIONE-S-TRANSFERASE AND GLUTATHIONE-PEROXIDASE

The effect of hypolipidaemic compounds on peroxisomal fatty acid beta- oxidation and on peroxisome morphology in the liver differs widely bet ween rodent and primate species. We studied the relative importance of peroxisomal and mitochondrial beta-oxidation of palmitate in primary cultures of hepatocytes isolated from rat and monkey liver in the abse nce or presence of clofibric acid or beclobric acid. It was demonstrat ed that it is possible to differentiate between peroxisomal and mitoch ondrial beta-oxidation activities in intact cells. Overall beta-oxidat ion of palmitate was ca. 30% higher in rat hepatocytes than in monkey liver cells. In both monkey and rat cell cultures the mitochondrial co mponent was over 90% of the total palmitate beta-oxidation. In rat hep atocyte culture clofibric acid and beclobric acid caused a 5- to 8-fol d stimulation of peroxisomal beta-oxidation, while in monkey cells thi s activity was not significantly increased. However, in cells derived from both species mitochondrial palmitate beta-oxidation was increased (rat 2.5-fold; monkey 1.5-fold). These results indicate that the spec ies differences in the increase in peroxisomal fatty acid oxidation ar e not a result of an inability to metabolize fatty acids in rat Liver cell mitochondria. A comparison of the activity of enzymes involved in the detoxification of hydrogen peroxide showed that catalase and glut athione-S-transferase activity is 2.9-fold higher in monkey hepatocyte s than in rat liver cells, while glutathione peroxidase activity was 1 .6-fold higher in rat cells. When a comparison between both species is made for the ratio of hydrogen peroxide production over catalase acti vity, it can be concluded that this peroxide will have much smaller po ssibilities to escape from the peroxisomal compartment in monkey hepat ocytes. These findings suggest that species differences in these enzym e activities can contribute to differences in susceptibility for perox isome proliferator-induced carcinogenicity between rodents and primate s.