Jang J J, Henneman J R, Kurata Y, Uno H, Ward J M
Tumor Pathology and Pathogenesis Section, NCI-FCRDC, Frederick, Maryland 21702-1201.
Cancer Lett. 1993 Jul 30;71(1-3):89-95. doi: 10.1016/0304-3835(93)90102-f.
The fate of placental glutathione S-transferase (GST-P)-immunoreactive hepatocytes, detectable in livers of rats soon after treatment with N-nitrosodiethylamine (DEN), was examined sequentially with or without phenobarbital (PB) promotion. Group 1 male F344/NCr rats were administered a single i.p. injection of 200 mg DEN per kg body weight at 5 weeks of age. Group 2 rats were given 500 ppm PB in the diet two weeks after the DEN treatment. Groups of six rats were sequentially sacrificed 16, 42, 70, 126 and 238 days after DEN injection. In DEN-treated rats, GST-P immunoreactive hepatocytes (single cells and multiple cell foci) were detectable 16 days after DEN, the total numbers decreasing by day 70 and thereafter rising again. In the early stages the proportion of single immunoreactive hepatocytes was prominent, but with time a gradual increase in small GST-P+ hepatocellular foci and larger foci became evident. Feeding of PB to rats for 16-238 days after a single DEN injection resulted in increases of both single cells and foci, especially foci composed of more than three hepatocytes. The growth response was increasingly pronounced with time. Adenomas or carcinomas were only observed at 126 or 238 days. Numbers of GST-P+ foci far exceeded the numbers of foci visible in hematoxylin-eosin (H & E) stained sections, and a few H & E foci were negative for GST-P. Many GST-P+ foci smaller than ten cells were composed of histologically normal hepatocytes. Almost all GST-P+ foci identifiable in H&E stained sections were larger than ten cells, consisted of clear cells (in both groups) or mixed (clear-eosinophilic) cells in PB-exposed rats, and appeared to be evenly distributed throughout the three zones of the liver. These results suggest that the promotive effect of PB is most evident as an increase in larger hepatocyte populations composed of more than three GST-P+ hepatocytes, rather than in increasing the populations of single GST-P immunoreactive cells. PB may cause clonal expansion of these single GST-P reactive hepatocytes. This study provides evidence for the hypothesis that some of the GST-P reactive hepatocytes are initiated cells.
在用N-亚硝基二乙胺（DEN）处理后不久，大鼠肝脏中可检测到的胎盘谷胱甘肽S-转移酶（GST-P）免疫反应性肝细胞的命运，在有或没有苯巴比妥（PB）促进的情况下进行了连续检查。第1组雄性F344/NCr大鼠在5周龄时腹腔注射一次，每千克体重注射200毫克DEN。第2组大鼠在DEN处理后两周，在饮食中给予500 ppm的PB。在DEN注射后16、42、70、126和238天，依次处死每组6只大鼠。在DEN处理的大鼠中，DEN注射后16天可检测到GST-P免疫反应性肝细胞（单个细胞和多个细胞灶），总数在第70天减少，此后再次上升。在早期，单个免疫反应性肝细胞的比例突出，但随着时间的推移，小的GST-P+肝细胞灶逐渐增加，较大的灶变得明显。在单次DEN注射后，给大鼠喂食PB 16 - 238天，导致单个细胞和灶均增加，尤其是由三个以上肝细胞组成的灶。随着时间的推移，生长反应越来越明显。仅在126天或238天观察到腺瘤或癌。GST-P+灶的数量远远超过苏木精-伊红（H&E）染色切片中可见的灶的数量，并且一些H&E灶对GST-P呈阴性。许多小于十个细胞的GST-P+灶由组织学上正常的肝细胞组成。在H&E染色切片中可识别的几乎所有GST-P+灶都大于十个细胞，在两组中均由透明细胞组成，在接触PB的大鼠中由混合（透明-嗜酸性）细胞组成，并且似乎均匀分布在肝脏的三个区带中。这些结果表明，PB的促进作用最明显的表现为，由三个以上GST-P+肝细胞组成的较大肝细胞群体增加，而不是单个GST-P免疫反应性细胞群体的增加。PB可能导致这些单个GST-P反应性肝细胞的克隆扩增。本研究为某些GST-P反应性肝细胞是起始细胞这一假说提供了证据。
