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.
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/cm3 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 et 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.
Conolly
R B
RB
Chemical Industry Institute of Toxicology, Six Davis Drive, Research Triangle Park, North Carolina 27709, USA.
Andersen
M E
ME
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002273:Carcinogens / Q000633:toxicity*; D003198:Computer Simulation; D019363:Cytochrome P-450 CYP1A1 / Q000032:analysis* / Q000096:biosynthesis; D019388:Cytochrome P-450 CYP1A2 / Q000032:analysis* / Q000096:biosynthesis; D004052:Diethylnitrosamine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000201:enzymology; D008954:Models, Biological; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D051381:Rats; D012189:Retrospective Studies
D002273:Carcinogens; D000072317:Polychlorinated Dibenzodioxins; D004052:Diethylnitrosamine; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2