Schulte-Hermann R, Timmermann-Trosiener I, Schuppler J
Carcinogenesis. 1986 Oct;7(10):1651-5. doi: 10.1093/carcin/7.10.1651.
Female rats received N-nitrosomorpholine to produce altered cell foci (potential cancer pre-stages) in the liver, followed by phenobarbital (PB) for 2 weeks. As indicators of adaptive responses we measured DNA synthesis cumulatively by infusion of [3H]thymidine for the entire period of PB treatment, and cytochrome P450-PB by immunocytochemistry on histological liver sections. Altered cell foci were identified by expression of gamma-glutamyltransferase (gamma-GT), and/or altered morphology. The following results were obtained. In normal parts of the liver PB induced DNA replication only in association with expression of P450-PB; both responses were restricted to the pericentral area of the liver lobule. In foci, PB treatment led to enhanced DNA synthesis. Furthermore, PB caused a 3-fold increase in the number of foci expressing cytochrome P450-PB, gamma-GT or both. Cumulative determination of DNA synthesis showed that this increase did not result from selective proliferation of single initiated cells. It is concluded that in foci also PB can induce expression of the adaptive increases in cytochrome P450-PB and DNA synthesis. Foci show the responses to PB more readily than normal hepatocytes, and irrespective of their position within the liver lobule. These findings suggest that expression of adaptive responses to inducing tumor promoters is facilitated in altered foci.
给雌性大鼠注射N-亚硝基吗啉，以在肝脏中产生改变的细胞灶（潜在的癌症前期阶段），随后给予苯巴比妥（PB）处理2周。作为适应性反应的指标，我们在整个PB处理期间通过输注[3H]胸苷来累积测量DNA合成，并通过对肝脏组织切片进行免疫细胞化学来检测细胞色素P450-PB。通过γ-谷氨酰转移酶（γ-GT）的表达和/或形态改变来识别改变的细胞灶。获得了以下结果。在肝脏的正常部位，PB仅在与P450-PB表达相关时诱导DNA复制；这两种反应都局限于肝小叶的中央周围区域。在细胞灶中，PB处理导致DNA合成增强。此外，PB使表达细胞色素P450-PB、γ-GT或两者的细胞灶数量增加了3倍。DNA合成的累积测定表明，这种增加不是由单个起始细胞的选择性增殖引起的。结论是，在细胞灶中，PB也可以诱导细胞色素P450-PB和DNA合成的适应性增加。细胞灶比正常肝细胞更容易显示对PB的反应，并且与它们在肝小叶内的位置无关。这些发现表明，在改变的细胞灶中，对诱导肿瘤促进剂的适应性反应的表达更容易。
