Evaluation of liver cell proliferation during ciprofibrate-induced hepatocarcinogenesis.
Evaluation of liver cell proliferation during ciprofibrate-induced hepatocarcinogenesis.
复制标题
环丙贝特诱导肝癌过程中肝细胞增殖的评价。
DOI：
10.1016/0304-3835(89)90172-9
复制
发表时间：
1989
期刊：
影响因子：
9.7
通讯作者：
Rao,MS
中科院分区：
文献类型：
--
作者：
Yeldandi,AV;Milano,M;Subbarao,V;Reddy,JK;Rao,MS
为了确定过氧化物酶体增殖剂的致癌潜力是否依赖于它们诱导细胞增殖的能力，我们研究了喂食过氧化物酶体增殖剂环丙贝特的大鼠肝脏中细胞增殖的程度。雄性大鼠喂食含有环丙贝特（0.025% w/w）的饮食，并在连续[3H]胸腺嘧啶标记1周后按选定的时间间隔杀死。标记指数的评估显示，第一周细胞增殖显著增加，但在治疗5周和20周结束时死亡的大鼠中没有。在服用环丙贝特40周和70周时发现肝细胞核标记增加，这与肝脏中假定的肿瘤前和肿瘤病变的出现相吻合。在短期饲养研究中，分别以0.025%和0.5%的日粮浓度给大鼠饲喂环丙贝特和乙喹，单独或联合饲喂7天。环丙贝特和乙氧喹单独或联合使用均可产生显著的肝肿大和DNA合成的显著增加，[3H]胸苷结合和放射自显影研究证实了这一点。同时服用环丙贝特和乙氧喹的动物的DNA合成略高于单独服用任何一种化合物的动物，这表明存在协同效应，尽管长期服用这两种药物会抑制肝癌的发生（Rao, ms . et al. (1984) Cancer Res, 44, 1072-1076）。本研究结果进一步表明，过氧化物酶体增殖剂诱导的细胞增殖在癌变中的作用可能不如这些化合物诱导的过氧化物酶体增殖。
To determine if the carcinogenic potential of peroxisome proliferators is dependent upon their ability to induce cell proliferation, we have investigated the extent of cell proliferation in the livers of rats fed ciprofibrate, a peroxisome proliferator. Male rats were maintained on a diet containing ciprofibrate (0.025% w/w) and killed at selected intervals following 1 week of continuous [3H]thymidine labeling. Evaluation of labeling indices demonstrated a significant increase in cell proliferation during the first week but not in rats killed at the end of 5 and 20 weeks of treatment. Increases in hepatocyte nuclear labeling were found at 40 and 70 weeks of ciprofibrate administration which coincided with the appearance in livers of putative preneoplastic and neoplastic lesions. In a short-term feeding study, ciprofibrate and ethoxquin were fed to rats at a dietary concentration of 0.025% and 0.5%, respectively, either alone or in combination for 7 days. Ciprofibrate and ethoxyquin either alone or in com- bination produced marked hepatomegaly and a significant increase in DNA synthesis as demonstrated by [3H]thymidine incorporation and autoradiographic studies. DNA synthesis in the group receiving ciprofibrate and ethoxyquin simultaneously, was slightly more than in animals that received either compound alone, suggesting a synergistic effect, although chronic feeding of these agents together resulted in inhibition of liver carcinogenesis (Rao, M.S. et al. (1984) Cancer Res., 44, 1072–1076). The results of this study further suggest that cell pro-liferation induced by peroxisome proli-ferators may be less important in carcinogenesis than peroxisome proliferation induced by these compounds.