Antioxidants and blockers of arachidonate metabolism inhibit the mitogenic effects of TPA in hepatocytes: differences in the operative mechanisms according to the cell cycle setting.

A single exposure to a low concentration (10(-10) mol/l) of TPA doubled the size of the fraction of neonatal rat hepatocytes flowing into DNA synthesis within 24 hours in 4-day-old primary cultures kept in low-calcium (0.01 mmol/l) HiWoBa2000 synthetic medium, thereby evoking a phenotypically neoplastic feature in normal, i.e. non-initiated cells. Inhibition kinetics studies, in which several antioxidants and blockers of the arachidonate cascade were given, each by itself, simultaneously with or at various time intervals after TPA, showed that the early mitogenic effects of TPA, i.e. the commitment of GO hepatocytes to grow and the reactivation of hepatocytes poised at the G1/S boundary required oxygen radicals and all the main metabolites of arachidonate. Instead, the subsequent flow into S phase of TPA-committed hepatocytes was not controlled by oxygen radicals and prostaglandins but by retinoid-modulable activities and by products of the lipoxygenase and thromboxane synthase pathways of arachidonate metabolism.