TUMOR-NECROSIS-FACTOR INDUCES ENZYMATIC CHANGES IN LIVER COMPARABLE TO THOSE IN EXTRAHEPATIC CANCER

Human recombinant tumor necrosis factor was administered to rats in sm all doses to determine whether it causes changes in the activity of li ver enzymes similar to those observed in cancer growing extrahepatical ly. Intraperitoneal injection of increasing doses of tumor necrosis fa ctor (20-100 mug/kg/day for 5 days) resulted in a 20-50% decrease in h epatic alanine aminotransferase (P less-than-or-equal-to 0.05), a 10-2 0% decrease in aspartate aminotransferase (P less-than-or-equal-to 0.0 4), and a 50-200% increase in alkaline phosphatase (P less-than-or-equ al-to 0.02). The activity of hepatic 5'-nucleotidase was unchanged. In the serum, there was no significant change in the activity of any of the enzymes. Histologically, there was no damage detectable by light o r electron microscopic examination of the liver, and no evidence of bi liary obstruction. However, in frozen liver sections stained histochem ically for alkaline phosphatase, there was a dramatic increase in the activity of this enzyme in hepatocytes, which was confined to the bile canaliculi. There was also a 3- to 9-fold increase in the mitotic act ivity of hepatocytes. Comparable changes have been reported in the tum or-free liver of animals with cancer.