Hepatic foci in rats after diethylnitrosamine initiation and 2,3,7,8-tetrachlorodibenzo-p-dioxin promotion: Evaluation of a quantitative two-cell model and of CYP 1A1/1A2 as a dosimeter
Hepatic foci in rats after diethylnitrosamine initiation and 2,3,7,8-tetrachlorodibenzo-p-dioxin promotion: Evaluation of a quantitative two-cell model and of CYP 1A1/1A2 as a dosimeter
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DOI：
10.1006/taap.1997.8248
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发表时间：
1997-10-01
影响因子：
3.8
通讯作者：
Andersen, ME
中科院分区：
文献类型：
--
作者：
Conolly, RB;Andersen, ME
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent hepatic tumor promoter in female rats. We used a quantitative, stochastic initiation-promotion model based on R. B. Conolly and J. S. Kimbell (Toxicol. Appl. Pharmacol. 124, 284-295, 1994) to analyze initiation-promotion results from a previously published study (H. C. Pitot et al., Carcinogenesis 8, 1491-1499, 1987) within the context of a negative selection model of tumor promotion. In this model, two types of initiated cells (called A and B cells) are produced by DEN initiation. Visually excellent correspondence between model predictions and data (i.e., foci/cm(3) liver and percentage of liver occupied by foci) are obtained when TCDD is described as having dose-responsive effects on division and death (apoptotic) rates of these two cell types. For A cells, both the division and the death rates increase while the difference between division and apoptotic rates decreases, For B cells, the difference between division and apoptotic rates increases, primarily due to a decrease in the apoptotic rate, We also linked these alterations in cell kinetics to a pharmacokinetic model for TCDD incorporating a five subcompartment model of the liver acinus with induction of CYP1A1 and 1A2 genes in the subcompartments, Alterations in A cell kinetics correlate with effects of TCDD in the region most sensitive to induction (subcompartment 5-centrilobular region); B cell dynamics correlate with induction in subcompartments 3-5 (centrilobular and mid-zonal regions). In summary, these modeling exercises show that (1) the two-cell model, without presuming effects of TCDD on the mutation rate of normal hepatocytes, reproduces the data of Pitot ef al, (1987) and (2) induction of CYP1A1/1A2 in different regions of the hepatic acinus can be used as a general correlate of these presumed changes in cell growth kinetics. (C) 1997 Academic Press.
