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

Abstract

Caffeic acid (CA, 3,, 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 immunohistochemical 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 0.40 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. © 1997 Soday of Toxicology.Caffeic acid (3,4-dihydroxycinnamic acid; CA), a natural phenolic antioxidant, is widely distributed in vegetables, fruits, and beverages (Herrmann, 1989). It occurs mainly in

Hormesis: A Highly Generalizable and Reproducible Phenomenon With Important Implications for Risk Assessment

“…These U-shaped dose-response relationships in two critical target organs display enhanced cellular division at the higher doses. Lutz et al (85) suggested that the low-dose response of a delayed cell division may account to some extent for the cancer-protective effect seen in previous bioassays as noted above.…”

“…(=) This hypothesis was subsequently evaluated by Lutz et aZ. (85) in which male F344 rats were fed caffeic acid at five different dietary concentrations including the controls (i.e., 0, 0.05, 0.14, 0.40, and 1.64 percent) for 4 weeks. The total number of epithelial cells per unit comparison in the forestomach was increased nearly 2.5-fold at the two highest concentrations, whereas no treatment effects were observed at 0.05 percent, the lowest dose studied.…”

Voltammetric Behavior of Tumor Cells U937 and Its Usefulness in Evaluating the Effect of Caffeic Acid

“…Caffeic acid is recognized to have potential effect in scavenging reactive species of oxygen and nitrogen [6]. However, there is no report on the effect of this chemical on tumor cells.…”

Investigation of J-shaped dose-responses induced by exposure to the alkylating agent N -methyl- N -nitrosourea

“…Indeed, MGMT has been hypothesized to be responsible for hormetic dose-responses following exposure to alkylating agents [44,45]. As MGMT is an inducible enzyme and repairs the highly mutagenic O 6 -methylguanine lesion, induction of MGMT would readily explain the reduction in mutant frequency observed by Thomas et al It is acknowledged that there may be additional underlying mechanisms for hormesis, which include but are not limited to alterations in apoptosis [46,47], [48], [49], [50] cell proliferation [42,51,52] and antioxidant capacity [53] , [54,55], [56], [57], [25] .…”