HEPATIC MITOCHONDRIAL ENZYME-ACTIVITY AND SERUM AMINO-ACID-COMPOSITION IN RATS TREATED WITH TUMOR-NECROSIS-FACTOR

The biochemical integrity of hepatocellular mitochondria was investiga ted in rats treated with small doses of human recombinant tumor necros is factor-alpha (Hur-TNF; 50-100 mu g/kg/d injected intraperitoneally for 5 d) by measuring the activities of three mitochondrial enzymes, g lutamate dehydrogenase, succinate dehydrogenase and malate dehydrogena se. The activity of glutamate dehydrogenase (a mitochondrial matrix en zyme) was 20% to 34% lower than that of control rats (P=0.02 to 0.0003 ). The activities of succinate dehydrogenase (an inner mitochondrial m embrane enzyme) and malate dehydrogenase (a mitochondrial matrix and c ytosolic enzyme) showed no significant difference. The effect of TNF o n serum amino acid composition was studied using pair-fed, weight-matc hed partners to eliminate any effect of the reduction of food intake d ue to TNF treatment. The results for the TNF-treated rats showed a sig nificant (P<0.05) increase in the concentration of 12 of the 21 amino acids measured (range = 33% to 140%). Of these, major increases were o bserved in the urea cycle intermediates, ornithine (140%) and arginine (59%), as well as proline (94%), alanine (41%), valine (61%), leucine (64%), isoleucine (63%), and aspargine (71%). Since previous studies have shown that the treatment of rats with the same low doses of TNF d id not cause any change in mitochondrial ultrastructure detectable by electron microscopy, these results suggest that significant biochemica l changes in amino acid metabolism occur as a result of a decrease in mitochondrial glutamate dehydrogenase activity.