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.
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.
复制标题
乳清酸内源水平的扰动和致癌作用：缺乏精氨酸的饮食和氨甲酰天冬氨酸对大鼠和小鼠肝癌发生的影响。
DOI：
10.1093/carcin/15.11.2497
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发表时间：
1994
期刊：
影响因子：
4.7
通讯作者：
Sarma,DS
中科院分区：
文献类型：
--
作者：
Vasudevan,S;Laconi,E;Rao,PM;Rajalakshmi,S;Sarma,DS
喂食过量的乳清酸（OA）在饮食中促进不同器官的致癌过程，包括肝脏。许多代谢和遗传疾病与内源性OA合成增加相关，其中一些疾病似乎会增加肝癌发展的风险。因此，本研究探讨是否过量的内源性OA也发挥促进作用，在小鼠和大鼠的肝癌发生。通过（i）饲喂精氨酸（AD）不足的饲料和（ii）饲喂过量的饲料氨甲酰天冬氨酸（CA）（OA合成的前体），实现OA内源性合成的增加。对雄性Fischer 344大鼠（200 mg/kg）或雄性DBA/2小鼠（90 mg/kg）腹膜内给予单剂量二乙基亚硝胺（DENA）。一周后，他们接受AD饮食或补充1.3%精氨酸（AS）的相同饮食，总共持续数周。第2周末行三分之二肝部分切除术（PH）。然后将所有动物转移至对照半合成基础饮食，共20周，然后处死。结果表明，AD饮食增加了大鼠（AD组中结节占据的面积百分比为4.7 ± 0.4，而对照值为0.7 ± 0.5）和小鼠（AD组中4/10只小鼠具有直径>5 mm的结节，而AS组中没有一只具有如此大的结节）中肝结节的发生率。在另一个实验中，同样用DENA启动的雄性Fischer 344大鼠暴露于基础饮食或含有2%CA的基础饮食4周，并在第二周结束时进行PH。在此方案之后，两组均饲喂基础饲料20周。给予CA的大鼠与在整个实验期间喂食基础饮食的对照组（0.07 ± 0.03 mm 3）相比产生更大的肝病灶和结节（0.84 ± 0.56 mm 3）。此外，AD饮食和饮食CA，像饮食OA一样，诱导肝尿苷核苷酸的增加。总之，这些结果表明，增加内源性合成的OA水平，如外源性供应的过量OA，可以诱导肝脏核苷酸库的不平衡，并可以对肝癌发生产生促进作用。
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 1.3% arginine (AS) for a total of 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 hepatlc 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 exo genously supplied excess OA, can induce an Imbalance in hepatic nucleotide pools and can exert a promoting effect on hepatocarcinogenesis.