Inhibition of DNA synthesis in primary cultures of hepatocytes by orotic acid.

Orotic acid has been shown to promote carcinogenesis in the liver and the intestine of the rat. In an attempt to determine whether orotic acid promotes liver carcinogenesis by creating differential mitoinhibition, experiments were designed to study the effect of orotic acid on the labeling index of isolated hepatocytes in response to epidermal growth factor. The results indicated that orotic acid added in vitro inhibited epidermal-growth-factor-induced labeling index of isolated hepatocytes. In addition, isolated hepatocytes from rats exposed to orotic acid under promoting conditions also exhibited a decreased response to epidermal growth factor. These data suggest that orotic acid may exert its promoting effect by differentially inhibiting the response of normal hepatocytes to one or more endogenous growth stimuli while permitting the initiated hepatocytes to respond to such stimuli and grow to form hepatic nodules.