Laconi E, Denda A, Rao P M, Rajalakshmi S, Pani P, Sarma D S
Department of Pathology, University of Toronto, Ontario, Canada.
Carcinogenesis. 1993 Sep;14(9):1771-5. doi: 10.1093/carcin/14.9.1771.
Our earlier studies indicated that orotic acid, a precursor for pyrimidine nucleotide biosynthesis, exerts a promoting effect on rat hepatocarcinogenesis. The present study was designed to determine the optimum conditions of exposure to orotic acid required for promotion of hepatocarcinogenesis in the initiated rats. The first series of experiments was designed to determine the optimum dose of orotic acid needed to exert its liver tumor promoting effect. Accordingly male Fischer rats were given diethylnitrosamine (200 mg/kg, i.p.) or 0.9% NaCl. One week later carcinogen-injected rats were divided into six groups and fed either basal diet or the same diet containing 0.1, 0.5, 1, 2 or 4% orotic acid. Rats given 0.9% NaCl were fed 4% orotic acid. Two-thirds partial hepatectomy was performed on all animals 10 weeks after starting on their respective diets, and all groups were killed 3 weeks thereafter. Analysis of gamma-glutamyltransferase-positive foci and nodules revealed that 0.5-1% orotic acid in the diet is sufficient to exert a significant promoting effect on the selective growth of initiated hepatocytes, while higher concentrations of orotic acid were only marginally more effective. No gamma-glutamyltransferase-positive foci were observed in animals given 4% orotic acid diet following saline injection. Using 1% orotic acid as the promoting regimen, in the next series, the minimum exposure time required for dietary orotic acid to promote liver carcinogenesis was determined. Male Fischer 344 rats were given i.p. either 1,2-dimethylhydrazine dihydrochloride (100 mg/kg) or 0.9% NaCl 18 h after 2/3 partial hepatectomy. After 1 week of recovery one group of rats was continued on a semisynthetic basal diet, while others were transferred to the same basal diet containing 1% orotic acid. Rats that were on the 1% orotic acid diet were progressively transferred to the basal diet after 5, 10, 20, 29 and 40 weeks of exposure. All rats were sacrificed 54 weeks after the beginning of the experiment. The results indicate that 100% of the initiated rats developed hepatic nodules whether or not they were exposed to an orotic acid-containing diet. However, the incidence of hepatocellular carcinoma was greatly increased in animals exposed to the orotic acid diet, with 42% incidence in initiated rats given orotic acid diet for 10 weeks and up to 75% in those exposed to this diet for 40 weeks. Further, promotion by orotic acid exhibited a high metastatic potential with 33-60% metastasis to the lungs.(ABSTRACT TRUNCATED AT 400 WORDS)
我们早期的研究表明，乳清酸作为嘧啶核苷酸生物合成的前体，对大鼠肝癌发生具有促进作用。本研究旨在确定在已启动肝癌发生的大鼠中促进肝癌发生所需的乳清酸暴露最佳条件。第一系列实验旨在确定发挥其肝肿瘤促进作用所需的乳清酸最佳剂量。相应地，给雄性Fischer大鼠腹腔注射二乙基亚硝胺（200mg/kg）或0.9%氯化钠。一周后，将注射致癌物的大鼠分为六组，分别喂食基础饲料或含0.1%、0.5%、1%、2%或4%乳清酸的相同饲料。给予0.9%氯化钠的大鼠喂食4%乳清酸。在开始各自的饮食10周后，对所有动物进行三分之二部分肝切除术，此后3周处死所有组。对γ-谷氨酰转移酶阳性灶和结节的分析表明，饮食中0.5%-1%的乳清酸足以对已启动的肝细胞选择性生长发挥显著促进作用，而更高浓度的乳清酸仅略有更明显的效果。注射生理盐水后喂食4%乳清酸饲料的动物未观察到γ-谷氨酰转移酶阳性灶。在下一系列实验中，以1%乳清酸作为促进方案，确定饮食中乳清酸促进肝癌发生所需的最短暴露时间。雄性Fischer 344大鼠在三分之二部分肝切除术后18小时腹腔注射二盐酸1,2-二甲基肼（100mg/kg）或0.9%氯化钠。恢复1周后，一组大鼠继续喂食半合成基础饲料，而其他大鼠转移至含1%乳清酸的相同基础饲料。喂食1%乳清酸饲料的大鼠在暴露5周、10周、20周、29周和40周后逐渐转移至基础饲料。在实验开始54周后处死所有大鼠。结果表明，无论是否暴露于含乳清酸的饮食，100%的已启动大鼠都出现了肝结节。然而，暴露于乳清酸饮食的动物肝细胞癌发生率大幅增加，喂食乳清酸饲料10周的已启动大鼠发生率为42%，暴露于该饮食40周的大鼠高达75%。此外，乳清酸促进作用表现出高转移潜能，肺转移率为33%-60%。（摘要截断于400字）
