Reduction of hepatocarcinogenesis by ursodeoxycholic acid in rats
Reduction of hepatocarcinogenesis by ursodeoxycholic acid in rats
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DOI：
10.1093/carcin/23.5.885
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发表时间：
2002-05-01
期刊：
影响因子：
4.7
通讯作者：
Kawasaki, H
中科院分区：
文献类型：
--
作者：
Oyama, K;Shiota, G;Kawasaki, H
熊去氧胆酸（UDCA）在世界范围内用于治疗原发性胆汁性肝硬化和慢性肝病。然而，其在肝癌发生中的作用仍有待探索。为了阐明其作用，进行了体内和体外实验。选用Fisher 344大鼠90只，分别饲喂标准饲粮（1组，n = 30）、添加0.1% UDCA（2组，n = 30）和0.3% UDCA（3组，n = 30）的标准饲粮。大鼠每周ig注射二乙基亚硝胺（DEN），连续6周。另外15只大鼠饲喂不加DEN处理的0.3% UDCA添加饲料（第4组）。末次注射DEN后5、10、18周处死大鼠。UDCA治疗可显著降低肝肿瘤数量和gst -p阳性肝细胞百分比。在18周时，UDCA使pcna阳性细胞减少。UDCA组5、10、18周时gst -p阴性区和18周时gst -p阳性区凋亡细胞数量增加。UDCA处理增加了线粒体中Bax和细胞质中细胞色素c的表达。UDCA组Caspase - 3活性也增加。UDCA添加到Huh7和Fao肝细胞癌（HCC）细胞培养中诱导细胞凋亡呈剂量依赖性。本研究的数据表明，UDCA治疗通过诱导“起始肝细胞”凋亡和抑制增殖来减少肝癌的发生。
Ursodeoxycholic acid (UDCA) is used worldwide for treatment of primary biliary cirrhosis and chronic liver diseases. However, its action on hepatocarcinogenesis remains to be explored. To clarify its effect, in vivo and in vitro experiments were performed. Ninety Fisher 344 rats were fed a standard diet (Group 1, n = 30), a standard diet supplemented with 0.1% UDCA (Group 2, n = 30) and 0.3% UDCA (Group 3, n = 30). The rats were given an i.p. injection of diethylnitrosamine (DEN) weekly for 6 weeks. Fifteen additional rats were fed 0.3% UDCA supplemented diet without DEN treatment (Group 4). The rats were killed at 5, 10 and 18 weeks after the last injection of DEN. The number of liver tumor and percentage of the GST-P-positive hepatocytes were significantly reduced by UDCA treatment. The PCNA-positive cells were decreased by administration of UDCA at 18 weeks. The increased number of apoptotic cells was observed in the GST-P-negative area at 5, 10 and 18 weeks and in the GST-P-positive area at 18 weeks in the UDCA group. Expression of Bax in mitochondria and cytochrome c in cytosol was increased by UDCA treatment. Caspase 3 activity was also increased in the UDCA groups. The addition of UDCA into the culture of Huh7 and Fao hepatocellular carcinoma (HCC) cells induced apoptosis in a dose-dependant manner. The data of the present study suggest that UDCA treatment reduces hepatocarcinogenesis via inducing apoptosis of 'initiated hepatocytes' as well as inhibiting proliferation.