© 1993 Oxford University Press
research-article |
The effect of long-term feeding of orotic acid on the incidence of foci of enzyme-altered hepatocytes and hepatic nodules in Fischer 344 rats
Department of Pathology, Medical Sciences Building, University of Toronto Toronto, Ontario, Canada M5S 1A8
1Istituto di Patologia Sperimentale, Universita di Cagliari Via Porcell 4, 09125 Cagliari, Italy
The present study was designed to determine the long-term effects of orotic acid (OA), a multi-organ tumor promoter, in rats not exposed to any carcinogen. Male Fischer 344 rats (130–150 g) were divided into two groups and given either a semisynthetic basal diet (BD) or the same diet containing 1% OA. Animals from both groups were killed after 1 or 2 years of treatment. Foci of placental glutathione-S-transferase (GST 7–7) positive hepatocytes were observed in the livers of both BD and OA fed rats killed after 1 year. However, they were more in number in animals receiving OA (156±21 versus 51±11/cm3). After 2 years, hepatic nodules were seen in almost all the animals given OA and in 
30% of the rats given BD. The nodules were of two main types: (i) a reddish-brown type, present in 85% of rats exposed to OA and in 27% of rats given BD, and (ii) a greyish-white type, found in 50% of animals fed OA and in none of the animals fed BD. These two types of lesions were also histologically different. Reddish-brown nodules were composed of slightly enlarged hepatocytes resembling normal surrounding tissue, while greyish-white nodules were similar in structure and are indistinguishable from hepatic nodules induced by genotoxic chemical carcinogens. The results are interpreted to suggest that the foci/nodules seen in OA-fed rats are due to a promoting effect of OA on spontaneously arising and/or diet-induced altered cells.