BACKGROUND In fulminant hepatic failure (FHF), the ability of surviving hepatocytes to proliferate is diminished. Therefore, it is important that medical therapy cause no further impairment of liver regeneration. In FHF, intracranial hypertension secondary to brain edema is the most common cause of brain injury and death and glycerol is used in some countries to treat this complication. Glycerol has been long known to suppress the growth of various cell types. We therefore decided to examine the effect of glycerol on hepatocyte proliferation in vitro and in vivo in rats subjected to partial (2/3) hepatectomy. Additionally, we investigated the effect of glycerol on the proliferation of HepG2 cells. MATERIALS AND METHODS Mitogen-induced primary rat hepatocytes were cultured in a hormonally defined Dulbecco's modified Eagle's medium containing increasing amounts of glycerol (0.5, 1.0, 2.0, 4.0%). HepG2 cells were cultured in minimal essential medium/10% FBS. After 2 days, HepG2 cells were exposed to glycerol (1.0-2.0-4.0%) and harvested after 48 h. Control dishes contained no glycerol. Cell proliferation was measured by the incorporation of [(3)H]thymidine and/or bromodeoxyuridine (BrdU). In vivo, Sprague-Dawley rats were subjected to standard partial 2/3 hepatectomy and assigned to intraportal administration of either 400 microl of glycerol or saline. Rats were killed after 1, 2, 3, 5, and 7 days. Liver weight/body weight ratio and BrdU uptake were measured. RESULTS In all cultures tested, glycerol suppressed the growth of cells in a dose-dependent manner. In vivo, a single intraportal dose of glycerol slowed the liver regenerative response. CONCLUSIONS This study demonstrated that glycerol has a potent growth-inhibitory effect on hepatocyte proliferation in vivo and in vitro. Remarkably, glycerol inhibited the proliferation of liver cancer cells as well. The results of this study have important clinical implications.