Kim D J, Lee K K, Hong J T
Department of Pathology, National Institute of Toxicology Research, Korea Food and Drug Administration, Seoul.
Arch Pharm Res. 1998 Aug;21(4):363-9. doi: 10.1007/BF02974627.
Glutathione S-transferase placental form (GST-P) positive foci development and its expression in liver exposed by nongenotoxic carcinogens phenobarbital (PB) and clofibrate (CF), and genotoxic carcinogen 2-amino-3-methylimidazo[4,5-f] quinoline (IQ) were investigated as a measure of carcinogenic potential of these chemicals. Male F344 rats were initially given a single intraperitioneal injection of diethylnitrosamine (200 mg/kg), and 2 weeks later, animals were fed diets containing 0.03% IQ or 0.5% CF or 0.05% PB or basal diet as a control for 6 weeks. All rats were subjected to two-thirds partial hepatectomy (PH) at week 3. Sequential sacrifice of rats was performed at 8 weeks or 52 weeks, and liver tissues were examined for immunohistochemical staining of GST-P positive foci. The numbers (No./cm2) and areas (mm2/cm2) of GST-P positive foci were increased by IQ or PB, but were decreased by CF compare to the control. Consistent with the development of GST-P positive foci, a time-related increase in the expression of GST-P mRNA was found in the rats treated with IQ, whereas CF decreased it. The incidence of hepatocellular carcinoma at 52 weeks was increased by all three chemicals. These results show that PB and IQ induced GST-P positive foci, but the peroxisome proliferator CF did not, which suggest that the prediction of carcinogenic potency based on the development of prenoplastic foci may cause false negative in a particular category compounds like peroxisome proliferators.
研究了谷胱甘肽S-转移酶胎盘型（GST-P）阳性灶的形成及其在非遗传毒性致癌物苯巴比妥（PB）和氯贝丁酯（CF）以及遗传毒性致癌物2-氨基-3-甲基咪唑[4,5-f]喹啉（IQ）暴露的肝脏中的表达，以此作为这些化学物质致癌潜力的一种衡量指标。雄性F344大鼠最初腹腔注射一次二乙基亚硝胺（200 mg/kg），2周后，动物分别喂食含0.03% IQ或0.5% CF或0.05% PB的饲料或基础饲料作为对照，持续6周。所有大鼠在第3周接受三分之二部分肝切除术（PH）。在第8周或第52周对大鼠进行分批处死，并对肝组织进行GST-P阳性灶的免疫组织化学染色检查。与对照组相比，IQ或PB使GST-P阳性灶的数量（个/cm²）和面积（mm²/cm²）增加，但CF使其减少。与GST-P阳性灶的形成一致，在用IQ处理的大鼠中发现GST-P mRNA表达随时间增加，而CF使其降低。所有三种化学物质均使52周时肝细胞癌的发生率增加。这些结果表明，PB和IQ诱导了GST-P阳性灶，但过氧化物酶体增殖剂CF没有，这表明基于癌前病灶形成来预测致癌效力可能会在过氧化物酶体增殖剂这类特定化合物中导致假阴性。
