FATTY-ACID OXIDATION, SUBSTRATE SHUTTLES, AND ACTIVITY OF CITRIC-ACID CYCLE IN HEPATOCELLULAR CARCINOMAS OF VARYING DIFFERENTIATION

Abstract

Fatty acid oxidation, reconstituted substrate shuttles and the activity of the citric acid cycle were studied in mitochondria isolated from Becker transplantable [rat] hepatocellular carcinoma H-252 and host livers, and the results were compared with those obtained with Morris hepatomas 7288CTC and 5123C. Whereas the activities of the malate-aspartate and the .alpha.-glycerophosphate shuttles were only slightly lower than those of host livers, the activity of the fatty acid shuttle was lower in H-252 mitochondria. O2 uptake and CO2 production assoicated with the oxidation of fatty acids was lower in tumors H-252 and 7288CTC, compared with host livers; tumor 5123C mitochondria show a high capacity to oxidize fatty acids. Ketogenesis and .beta.-hydroxybutyrate dehydrogenase activity were also lower in H-252 tumor mitochondria. Neither O2 uptake associated with the oxidation of other respiratory substrates nor CO2 production from labeled citric acid cycle intermediates was impaired in tumor H-252 or 7288CTC. CO2 production from succinate or malate was elevated in these tumors. These factors suggest that the respiratory phosphorylation chain and activity of the citric acid cycle are fully functional in tumors H-252 and 7288CTC. The defects responsible for the lower rates of fatty acid oxidation in these tumors probably involves the .beta.-oxidation pathway, as well as the activation of fatty acids. The impairment of fatty acid oxidation may explain the lower activity of the reconstituted fatty acid shuttle for transporting reducing equivalents into H-252 mitochondria. The different properties with regard to fatty acid oxidation in Morris hepatoma 5123C, compared with those in Becker H-252 and Morris hepatoma 7288CTC, may reflect the different extent of differentiation in these tumors, the former being a slow growing, well-differentiated tumor; the latter represent tumors that are less differentiated and of more rapid growth rate.