Tumor promoting phorbol-ester derivatives increase ornithine decarboxylase activity and polyamine biosynthesis in the liver of the rat and mouse.

Abstract

The ability of the phorbol-ester tumor promoters to alter ornithine decarboxylase (ODC) activity in the liver of the rat and mouse was determined. The injection of 12-O-tetra-decanoyl phorbol-13-acetate (TPA, 100 microgram, i.p.) led to a 250-fold increase in hepatic ODC activity within 4 h of administration. This increase in ODC activity required both RNA and protein synthesis and did not occur when a variety of the non-tumor promoting phorbol-ester derivatives were administered to the rat. A distinct dose-dependent increase in hepatic ODC activity could be observed at 4 h following the injection of increasing amounts of TPA (0-100 microgram, i.p.). As little as 1.0 microgram TPA (i.p.) administered to a rat resulted in a significant stimulation in the activity of ODC in the liver compared to the control unstimulated values. Both 200 micrograms and 500 micrograms TPA produced less of an elevation in hepatic ODC activity than did the optimal dose of 100 micrograms. In the mouse, the administration of 1 microgram and 20 micrograms of TPA (i.p.) both led to a marked increase in hepatic ODC activity at 7 h and 4 h, respectively, following injection. A 4-5-fold increase in putrescine levels occurred in the rat liver in a biphasic manner between 4-8 h and 16-24 h following the injection of TPA (100 micrograms). No alterations in either spermidine or spermine were observed during this period. The administration of 100 micrograms of TPA to the rat did not alter the incorporated control animals. Under these identical conditions partial hepatectomy led to a large increase in DNA synthesis.