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© 1997 Oxford University Press

other

Dose Response for the Stimulation of Cell Division by Caffeic Acid in Forestomach and Kidney of the Male F344 Rat

Ursula Lutz*, Serena Lugli{dagger}, Annette Bitsch*, Josef Schlatter{ddagger} and Werner K. Lutz*,1

*Department of Toxicology, University of Würzburg D-97078 Würzburg, Germany {dagger}Institute of Toxicology, ETH and University of Zürich CH-8603 Schwerzenbach, Switzerland {ddagger}Swiss Federal Office of Public Health, Food Sciences Division, c/o Institute of Veterinary Pharmacology CH-8057 Zürich, Switzerland

Received March 27, 1997; accepted June 27, 1997

Caffeic acid (CA, 3,4-dihydroxycinnainic acid), at 2% in the diet, had been shown to be carcinogenic in forestomach and kidney of F344 rats and B6C3F1 mice. Based on its occurrence in coffee and numerous foods and using a linear interpolation for cancer incidence between dose 0 and 2%, the cancer risk in humans would be considerable. In both target organs, tumor formation was preceded by hyperplasia, which could represent the main mechanism of carcinogenic action. The dose-response relationship for this effect was investigated in male F344 rats after 4-week feeding with CA at different dietary concentrations (0, 0.05, 0.14, 0.40, and 1.64%). Cells in S-phase of DNA replication were visualized by iminunohistochemical analysis of incorporated 5-bromo-2'-deoxyuridine (BrdU), 2 hr after intraperitoneal injection. In the forestomach, both the total number of epithelial cells per millimeter section length and the unit length labeling index of BrdU-positive cells (ULLI) were increased, about 2.5-fold, at 0.44) and 1.64%. The lowest concentration (0.05%) had no effect. At 0.14%, both variables were decreased by about one-third. In the kidney, the labeling index in proximal tubular cells also indicated a J-shaped (or U-shaped) dose response with a 1.8-fold increase at 1.64%. In the glandular stomach and in the liver, which are not target organs, no dose-related effect was seen. The data show a good correlation between the organ specificity for cancer induction and stimulation of cell division. With respect to the dose-response relationship and the corresponding extrapolation of the animal tumor data to a human cancer risk, a linear extrapolation appears not to be appropriate.


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