The tumor promoters TPA, phenobarbital, and nafenopin and the prostaglandins of A, E, and F series overcome the G1/S block imposed by extracellular calcium deprivation on neonatal rat hepatocytes.

A single exposure to a low concentration (10(-9) mole/l) of exogenous arachidonic acid or of prostaglandins of A, E, and F series significantly stimulated primary neonatal rat hepatocytes to enter S phase irrespective of whether the extracellular calcium concentration was high (i.e., 1.8 mmole/l) or markedly reduced (i.e., 0.01 mmole/l). Similarly, a single treatment with an even smaller (10(-10) mole/l) dose of the known tumor promoters 12-O-tetradecanoylphorbol-13-acetate (TPA), phenobarbital, and nafenopin enhanced hepatocytic DNA synthesis when the environmental calcium level was both high and low. By contrast, a single application of a small concentration (10(-11)-10(-10) mole/l) of hormones such as epidermal growth factor (EGF), glucagon, and insulin, and of drugs such as imidazole and indomethacin only increased the hepatocytic flow into DNA synthesis when the extracellular calcium was high. These findings reveal that the mechanisms of physiological or pharmacological, calcium-dependent stimulation of hepatocellular growth are likely to be different from those of pathological, calcium-independent stimulation, as the latter, but not the former, would involve prostaglandin-mediated metabolic processes.