Fatty acid oxidation, substrate shuttles, and activity of the citric acid cycle in hepatocellular carcinomas of varying differentiation.

Fatty acid oxidation, reconstituted substrate shuttles, and the activity of the citric acid cycle were studied in mitochondria isolated from Becker transplantable 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 much lower in H-252 mitochondria. Oxygen uptake and CO2 production associated with the oxidation of fatty acids was much lower in tumors H-252 and 7288CTC, compared with host livers, whereas tumor 5123C mitochondria show a high capacity to oxidize fatty acids. Ketogenesis and beta-hydroxybutyrate dehydrogenase activity were also lower in tumor H-252 mitochondria. However, neither oxygen uptake associated with the oxidation of other respiratory substrates nor CO2 production from succinate or malate was strikingly 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 responsbile 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, whereas the latter represent tumors that are less differentiated and of more rapid growth rate.