Luebeck E G, Moolgavkar S H, Buchmann A, Schwarz M
Fred Hutchinson Cancer Research Center, Public Health Sciences Division, Seattle, Washington 98104.
Toxicol Appl Pharmacol. 1991 Dec;111(3):469-84. doi: 10.1016/0041-008x(91)90251-9.
The promotional effect of various polychlorinated biphenyls and phenobarbital on enzyme-altered lesions in the rat liver was quantified within the framework of the two-stage carcinogenesis model of Moolgavkar and colleagues. The experiment analyzed here followed an initiation-promotion protocol in which female Wistar rats were initiated with diethylnitrosamine (DEN) at 10 mg/kg body wt for 10 days followed by a 8-week period of promoter treatment with various cytochrome P450 isoenzyme inducing and noninducing compounds. This analysis included 4-monochlorobiphenyl, 2,2',4,5'-tetrachlorobiphenyl, 3,3',4,4'-tetrachlorobiphenyl and 3-methylcholanthrene, all administered at 150 mumol/kg body wt, and phenobarbital which was administered continuously in the diet at 0.05% until termination. Animals were killed either 1 or 9 weeks after the end of treatment and their livers were examined for enzyme histological alterations. Focal transections were classified as falling into three phenotypic categories: ATPase dominant, GGT dominant, or ATPase plus GGT (coextensive). A quantitative method was used to analyze the data consisting of the number and sizes of the focal transections. The number of cells altered by the DEN treatment and cell kinetic parameters measuring the promotional effect of the various compounds were estimated. On the basis of these estimates, we computed the number of nonextinct altered foci and their volume fraction as functions of time. We found that foci exhibiting the coextensive phenotype respond most efficiently to promoter treatment, while GGT dominant foci respond weakly to all the promoters with the exception of 3-MC. For phenobarbital, we observed a significant slowing of focal cell proliferation over time.
在穆尔加夫卡尔及其同事的两阶段致癌模型框架内，对各种多氯联苯和苯巴比妥对大鼠肝脏中酶改变性病变的促进作用进行了量化。此处分析的实验遵循启动-促进方案，其中雌性Wistar大鼠以10 mg/kg体重的剂量给予二乙基亚硝胺（DEN），持续10天，随后用各种细胞色素P450同工酶诱导和非诱导化合物进行8周的促进剂处理。该分析包括4-一氯联苯、2,2',4,5'-四氯联苯、3,3',4,4'-四氯联苯和3-甲基胆蒽，均以150 μmol/kg体重的剂量给药，苯巴比妥则以0.05%的浓度持续添加在饲料中直至实验结束。在处理结束后1周或9周处死动物，并检查其肝脏的酶组织学改变。局灶性横切面被分类为三种表型类别：ATP酶主导型、γ-谷氨酰转移酶（GGT）主导型或ATP酶加GGT（共同扩展型）。使用定量方法分析由局灶性横切面的数量和大小组成的数据。估计了经DEN处理改变的细胞数量以及测量各种化合物促进作用的细胞动力学参数。基于这些估计值，我们计算了未消失的改变灶数量及其体积分数随时间的变化函数。我们发现，表现出共同扩展表型的病灶对促进剂处理反应最有效，而GGT主导型病灶除对3-甲基胆蒽外，对所有促进剂的反应都较弱。对于苯巴比妥，我们观察到随着时间的推移，局灶性细胞增殖显著减缓。
