Regular Article
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

https://doi.org/10.1006/taap.1997.8248Get rights and content

Abstract

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. Pitotet al., Carcinogenesis8,1491–1499, 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/cm3liver 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 Pitotet 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.

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