DOSE-DEPENDENT BIPHASIC EFFECTS OF PHENOBARBITAL ON GROWTH AND DIFFERENTIATION OF PRIMARY CULTURE RAT HEPATOCYTES

The actions of phenobarbital, a liver tumour promoter, on growth and d ifferentiation of primary culture normal rat hepatocytes change biphas ically as a function of its concentration. At low concentrations of 0. 5-2 mmol/L, phenobarbital enhances DNA synthesis of normal adult rat h epatocytes in the presence of epidermal growth factor (EGF) and/or dex amethasone. This is also true for normal suckling (1-2-week-old) rat h epatocytes, without added growth factor(s), in serum-free primary cult ure. Contrarily, phenobarbital at high concentrations (3-4 mmol/L) sup presses DNA synthesis of suckling rat hepatocytes. Furthermore, phenob arbital inhibits DNA synthesis of transforming growth factor-alpha-sti mulated primary hepatocytes from normal adult rats in a dose-dependent manner within a concentration range of 3-6 mmol/L. When normal adult rat: hepatocytes are led to undergo multiple proliferative cycles upon stimulation with hepatocyte growth factor (HGF) and EGF in the chemic ally defined hepatocyte growth medium (HGM), 3 mmol/L phenobarbital al so remarkably suppresses DNA synthesis. Phenobarbital at 3 mmol/L effe ctively keeps these hepatocytes morphologically differentiated and acc elerates restoration of the expression of markers characteristic of di fferentiated cells after che initial cellular growth phase. In additio n, phenobarbital efficiently supports prolonged survival of the hepato cytes.