Promotion by orotic acid of liver carcinogenesis in rats initiated by 1,2-dimethylhydrazine

Abstract

Our earlier experiments revealed that orotic acid, a precursor for pyrimidine nucleotides, selectively stimulated the growth of carcinogen-modified liver cells to grow into enzyme-altered hepatocytes (Cancer Lett., 16: 191-196, 1982). The present study was designed to determine whether prolonged feeding of orotic acid will result in hepatocellular carcinoma in initiated rats. Accordingly, groups of rats were given i.p. either 1,2-dimethylhydrazine dihydrochloride (100 mg/kg) or an equivalent volume of 0.9% sodium chloride solution 18 hr after two-thirds partial hepatectomy. After 1 week of recovery, they were continued on either the basal diet or the basal diet containing 1% orotic acid for 10 to 13 months. Some groups of rats, in addition, received a single necrogenic dose of CCl4 8 weeks following exposure to orotic acid diet. The results obtained indicated that 87.5% of initiated rats exposed to orotic acid developed hepatocellular carcinomas in 10 months and 100% in 13 months. Initiated rats exposed to orotic acid diet coupled with a single administration of CCl4 developed 100% hepatocellular carcinoma by 10 months. In contrast, the incidence of hepatocellular carcinoma in initiated rats fed basal diet alone for 13 months was 37.5%, while, in those that received CCl4 in addition, the incidence was 25% in 10 months. Interestingly, a significant number of liver cancers (29 to 36%) in the orotic acid-fed group metastasized to lungs, whereas none of the liver cancers in rats exposed to basal diet metastasized.(ABSTRACT TRUNCATED AT 250 WORDS)