ABNORMAL GLUTATHIONE AND SULFATE LEVELS AFTER INTERLEUKIN-6 TREATMENTAND IN TUMOR-INDUCED CACHEXIA

Excessive urea excretion associated with a negative nitrogen balance a nd massive loss of skeletal muscle mass (cachexia) is a frequent life- threatening complication in malignancies and HIV infection. As these p atients have often elevated interleukin-6 (IL-6) and abnormally low cy stine levels, we have now determined the intracellular levels of gluta thione and other cysteine derivatives in the liver and muscle tissue o f IL-6-treated or tumor-bearing C57BL/6 mice, IL-6 treatment or inocul ation of the MCA-105 fibrosarcoma caused a significant increase in hep atic gamma-glutamyl-cysteine synthetase activity and a decrease in the sulfate level, glutamine/urea ratio, and glutamine/glutamate ratio, s uggesting that a decrease of the proton generating cysteine catabolism in the liver may increase carbamoyl-phosphate synthesis and urea form ation at the expense of net glutamine synthesis. Treatment with cystei ne, conversely, caused an increase in sulfate, gluzamine/urea ratios, and glutamine/glutamate ratios and may thus be a useful therapeutic to ol in clinical medicine, In contrast to the liver, muscle tissue of tu mor-bearing mice showed decreased glutathione and increased sulfate le vels, suggesting that the cysteine pool may be drained by an increased cysteine catabolism in this tissue, The findings indicate that tumor cachexia is triggered initially by IL-6 and is later sustained by proc esses driven by an abnormal cysteine metabolism in different organs.