Vasudevan S, Laconi E, Rao P M, Rajalakshmi S, Sarma D S
Department of Pathology, University of Toronto, Ontario, Canada.
Carcinogenesis. 1994 Nov;15(11):2497-500. doi: 10.1093/carcin/15.11.2497.
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.
在饮食中摄入过量乳清酸（OA）会促进包括肝脏在内的不同器官的致癌过程。许多代谢和遗传紊乱与内源性OA合成增加有关，其中一些紊乱似乎会增加肝癌发生的风险。因此，本研究探讨内源性来源的过量OA是否也会对小鼠和大鼠的肝癌发生起到促进作用。通过以下两种方式实现内源性OA合成增加：（i）喂食精氨酸缺乏饮食（AD）；（ii）喂食过量的氨基甲酰天冬氨酸（CA），它是OA合成的前体。给雄性Fischer 344大鼠（200 mg/kg）或雄性DBA/2小鼠（90 mg/kg）腹腔注射单剂量的二乙基亚硝胺（DENA）。一周后，将它们置于AD饮食或补充有1.35%精氨酸的相同饮食（AS）中，共4周。在第二周结束时进行三分之二部分肝切除术（PH）。然后将所有动物转移至对照半合成基础饮食中，共20周，之后处死。结果表明，AD饮食增加了大鼠（AD组结节所占面积百分比为4.7±0.4，而对照组为0.7±0.5）和小鼠（AD组10只小鼠中有4只出现直径>5 mm的结节，而AS组无如此大的结节）肝脏结节的发生率。在另一项实验中，同样用DENA启动的雄性Fischer 344大鼠，暴露于基础饮食或含2% CA的基础饮食中4周，并在第二周结束时进行PH。之后两组均喂食基础饮食20周。与整个实验期间喂食基础饮食的对照组（0.07±0.03 mm³）相比，给予CA的大鼠形成了更大的肝灶和结节（0.84±0.56 mm³）。此外，AD饮食和饮食中的CA，与饮食中的OA一样，都会导致肝脏尿苷核苷酸增加。综上所述，这些结果表明，内源性合成的OA水平升高，与外源性供应的过量OA一样，会导致肝脏核苷酸库失衡，并对肝癌发生起到促进作用。
