Tiwawech D, Hasegawa R, Kurata Y, Tatematsu M, Shibata M A, Thamavit W, Ito N
First Department of Pathology, Nagoya City University Medical School, Japan.
Carcinogenesis. 1991 Jun;12(6):985-90. doi: 10.1093/carcin/12.6.985.
Dose-dependent development of pre-neoplastic liver cell foci induced by 2-acetylaminofluorene (2-AAF) was investigated in relation to cell-proliferative activity. Male F344 rats were initially given a single i.p. injection of diethylnitrosamine (DEN, 200 mg/kg) and starting 2 weeks later received diets containing 2-AAF at dose levels of 150, 100, 60, 45, 35 or 30 p.p.m., 500 p.p.m. phenobarbital (PB) or basal diet as a control for 6 weeks. Two-thirds partial hepatectomy (PH) was performed at week 3. The rats were sequentially killed from weeks 0 to 16 and liver sections were analysed by double staining for both BrdU incorporation and glutathione S-transferase placental form (GST-P) expression. 2-AAF increased numbers and areas of GST-P positive (GST-P+) foci in a dose-dependent manner, especially after PH. Proliferation of hepatocytes, as indicated by BrdU labelling indices (LI), was higher in GST-P+ foci than in surrounding hepatocytes in all 2-AAF-treated groups, even after cessation of carcinogen administration. Proliferative response of hepatocytes to PH was delayed in rats treated with the highest dose of 2-AAF in both foci and in surrounding areas possibly due to the 2-AAF toxicity. In the PB treated group, the results were similar to those for the lower dose 2-AAF-treated groups. It is concluded that the development of GST-P+ foci and cell proliferation in GST-P+ foci are directly related to 2-AAF treatment in a dose-dependent manner and the present assay system is reliable for detection of carcinogenicity of chemicals even at low doses.
研究了2-乙酰氨基芴（2-AAF）诱导的癌前肝细胞灶的剂量依赖性发展与细胞增殖活性的关系。雄性F344大鼠最初腹腔注射一次二乙基亚硝胺（DEN，200mg/kg），2周后开始接受含150、100、60、45、35或30ppm剂量水平的2-AAF、500ppm苯巴比妥（PB）的饲料或基础饲料作为对照，持续6周。在第3周进行三分之二部分肝切除术（PH）。从第0周到第16周依次处死大鼠，肝切片通过双重染色分析BrdU掺入和谷胱甘肽S-转移酶胎盘形式（GST-P）表达。2-AAF以剂量依赖性方式增加GST-P阳性（GST-P+）灶的数量和面积，尤其是在PH后。在所有2-AAF处理组中，BrdU标记指数（LI）表明，GST-P+灶中的肝细胞增殖高于周围肝细胞，即使在停止给予致癌物后也是如此。在灶区和周围区域，用最高剂量2-AAF处理的大鼠肝细胞对PH的增殖反应延迟，这可能是由于2-AAF的毒性。在PB处理组中，结果与低剂量2-AAF处理组相似。结论是，GST-P+灶的发展和GST-P+灶中的细胞增殖与2-AAF处理呈剂量依赖性直接相关，并且本检测系统对于检测化学物质的致癌性即使在低剂量下也是可靠的。
