Perturbations of endogenous levels of orotic acid and carcinogenesis: effect of an arginine-deficient diet and carbamyl aspartate on hepatocarcinogenesis in the rat and the mouse.

Abstract

Feeding excess orotic acid (OA) in the diet promotes the carcinogenic process in different organs including the liver. A number of metabolic and genetic disorders are associated with increased synthesis of endogenous OA and some of these disorders appear to pose an increased risk of liver cancer development. This study therefore examines whether excess OA of endogenous origin also exerts a promoting effect on hepatocarcinogenesis in the mouse and the rat. Increased endogenous synthesis of OA was achieved by (i) feeding a diet deficient in arginine (AD) and (ii) feeding excess dietary carbamylaspartate (CA), a precursor for the synthesis of OA. A single dose of diethylnitrosamine (DENA) was given i.p. to male Fischer 344 rats (200 mg/kg) or to male DBA/2 mice (90 mg/kg). One week later they were placed on either AD diet or the same diet supplemented with 1.35% arginine (AS) for a total of 4 weeks. Two-thirds partial hepatectomy (PH) was performed at the end of the second week. All animals were then transferred to a control semisynthetic basal diet for a total of 20 weeks before they were killed. The results indicated that AD diet increased the incidence of hepatic nodules in both rats (percentage area occupied by nodules was 4.7 +/- 0.4 in the AD group compared to a control value of 0.7 +/- 0.5) and mice (4/10 mice had nodules > 5 mm diameter in the AD group while none in the AS group had such large nodules). In another experiment male Fischer 344 rats similarly initiated with DENA were exposed to either basal diet or basal diet containing 2% CA for 4 weeks coupled with PH performed at the end of the second week. This regimen was followed by 20 weeks of feeding basal diet to both groups. Rats given CA developed larger hepatic foci and nodules (0.84 +/- 0.56 mm3) compared to the control group, which was fed basal diet throughout the experiment (0.07 +/- 0.03 mm3). Further, both AD diet and dietary CA, like dietary OA, induced an increase in hepatic uridine nucleotides. Taken together, these results suggest that increased levels of endogenously synthesized OA, like exogenously supplied excess OA, can induce an imbalance in hepatic nucleotide pools and can exert a promoting effect on hepatocarcinogenesis.