ESTIMATION OF METABOLIC FLUX RATES IN LIVER PURINE CATABOLISM OF TUMOR-BEARING MICE BY COMPUTER-SIMULATION OF RADIOACTIVE-TRACER EXPERIMENTS

Mouse hepatocytes from healthy control mice and from Ehrlich ascites t umour-bearing mice were used for tracer-kinetic studies of purine cata bolism of liver cells during different periods of tumour growth. The d ynamics of the radioactive tracers were modelled mathematically by a s ystem of differential equations. Computer simulations, i.e. direct fit ting of numerical solutions of these equations to the observed time-co urses of metabolites and specific radio-activites, enables one to esti mate unknown kinetic parameters of a simplified model of pathways of h epatic purine catabolism in tumour-bearing mice. There occurred great differences of metabolic flux rates between control hepatocytes, hepat ocytes of mice during the proliferating period of tumour growth (6th d ay after inoculation of the tumour) and hepatocytes of mice during the resting period of tumour growth (12th day after inoculation of the tu mour). The final purine degradation of hepatocytes prepared during the proliferating period was lower in comparison with that of control hep atocytes, but it was markedly higher in hepatocytes prepared during th e resting period of tumour growth. The changes in hepatocyte purine ca tabolism during the proliferating period of tumour growth argue for tr ansitions which aim at the maintenance of high purine nucleotide level s in the liver itself rather than for an increased nucleoside and nucl eobase supply for the tumour. This suggestion is in accordance with th e increased ATP level of the liver during the proliferating phase of t umour growth. The drastic acceleration of the final steps of hepatic p urine catabolism forming uric acid and allantoin during the resting pe riod of tumour growth was predominantly due to increased Awe rate from xanthosine and guanine in accordance with increased catabolism of mon ophosphorylated nucleotides.