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

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

Ursula Lutz 0 1 Serena Lugli.t Annette Bitsch 0 1 Josef Schlatter 0 Werner K. Lutz 0 1 0 1997 Soday of Toxicology 1 Department of Toxicology, University of WUrzburg , D-97078 WUrzburg , Germany 2 Institute of Toxicology, ETH and University of Zurich , CH-8603 Schwerzenbach , Switzerland; and $Swiss Federal Office of Public Health, Food Sciences Division, do Institute of Veterinary Pharmacology , CH-8057 Zurich , Switzerland Caffeic acid (CA, 3,4-dihydroxycinnamic 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 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 - 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 conjugated forms. In chlorogenic acid, the most abundant derivative, the carboxylic acid function of CA is linked with a hydroxyl group of quinic acid. CA, as other polyphenols, has attracted attention for having both hazardous and beneficial effects [review (Stich, 1991)]. Administered at 2% in the diet for 2 years, CA was shown to induce hyperplasia and tumors in the forestomach and kidney of F344 rats and B6C3F1 mice (Hagiwara et al, 1991). When administered to male F344 rats after initiation with 7V-methyl-W-nitro-/V-nitrosoguanidine (MNNG), 0.5% CA in the diet for 35 weeks (Hirose et al., 1991) or 1% CA for 51 weeks (Hirose et al, 1992) increased the incidence of forestomach tumors observed after initiation with MNNG alone. Treatment of female Sprague-Dawley rats with 0.5% CA for 51 weeks after initiation with 7,12-dimethylbenz[a]anthracene also resulted in a higher incidence of forestomach tumors (Hirose et al, 1988). On the other hand, CA at 0.05% for 32 weeks inhibited the formation of squamous epithelial carcinomas of the rat tongue induced by 4-nitroquinoline-loxide given for 5 weeks (Tanaka et at, 1993) and of mouse forestomach tumors induced by benzo(a)pyrene (at 0.54% CA) (Wattenberg et al, 1980). Thus, CA was shown to be carcinogenic at 2%, tumor-promoting activity was shown at 0 . 5 - 1 % , and anticarcinogenic effects at 0.05-0.5%. Exposure of humans to CA strongly depends on the coffee consumption. Moderately high consumers may ingest about 9 mg/kg body wt per day. The intake from foods, mainly from tomatoes and potatoes, was estimated to be about 0.2 mg/kg body wt per day (National Research Council, 1996). The human cancer risk, linearly extrapolated from the animal tumor data to a dose of 1 mg/kg body wt per day would result in a value as high as 1 in 1000 lives (Lutz and Schlatter, 1992). A linear extrapolation to the human exposure level might be appropriate for DNA-reactive carcinogens. For CA, this mechanism of action is unlikely. CA showed no mutagenic effects in different bacterial test systems. On the other hand, forward mutations were induced in cultured mouse lymphoma L5178Y cells, and chromosomal aberrations were induced in cultured Chinese hamster ovary cells 0272-0590/97 $25.00 Copyright 1997 by the Society of Toxicology. All rights of reproduction in any form reserved. (Hanham et al, 1983). In the IARC monograph on CA it was concluded that indirect genotoxicity via reactive oxygen species or tumor-promoting activity, possibly based on the stimulation of cell division, might be more relevant than DNA reactivity (IARC, 1993). For this mechanism of action, nonlinear dose-response relationships are more widely accepted. Therefore, (...truncated)


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Ursula Lutz, Serena Lugli, Annette Bitsch, Josef Schlatter, Werner K. Lutz. Dose Response for the Stimulation of Cell Division by Caffeic Acid in Forestomach and Kidney of the Male F344 Rat, Toxicological Sciences, 1997, pp. 131-137, 39/2, DOI: 10.1093/toxsci/39.2.131