Dietary orotic acid enhances the incidence of {gamma}-glutamyltransferase positive foci in rat liver induced by chemical carcinogens

Feeding male Fischer F-344 rats for 5 weeks a diet containing1% orotic acid, a precursor for pyrimidine nucleotide biosynthesis,resulted in an increased incidence of -glutamyltrans-ferase(EC 2.3.2.2[EC]) positive foci induced by chemical carcinogens including1,2-dimethylhydrazine, diethylnitrosamine, benzo[a]pyrene, andaflatoxin B₁. This unique effect of orotic acid can be accentuatedby supplying a liver cell proliferative stimulus. The enzymealtered hepatocytes have a higher labelling index (4.4%) comparedwith that of the hepatocytes in the surrounding liver (0.26%).The effect of orotic acid on the increased incidence of focicannot be attributed to either the induction of liver cell proliferationor the imposition of a preferential inhibitory effect on theproliferation of normal hepatocytes while permitting the carcinogen-modifiedhepatocytes to respond to an endogenous or exogenous liver cellproliferative stimulus and grow to form foci. Orotic acid alsodid not behave like some of the promoters of liver carcinogenesissuch as phenobarbital and polychlorinated biphenyls in thatit did not induce either the phase I or phase II componentsof hepatic drug metabolizing enzyme systems. Some of the possiblemechanisms by which orotic acid enhances the incidence of -glutamyltransferasepositive foci by carcinogens are discussed.