Phenolic acids such as caffeic acid (CA) and ferulic acid (FA) are widely distributed in plant material in both free and combined forms and, as such, are components of the human diet. However, less is know on their effects when applied parenterally. The physiological relevance of CA and FA is suggested to be represented by their antioxidant action in vivo (Iwahashi et al., 1990; Graf, 1992; Nardini et al., 1997, 1998). This effect seems to be due to the ability of CA to reduce GSH depletion and to inhibit lipid peroxidation during t-butyl-hydroperoxide-induced oxidative stress (Nardini et al., 1998). It can be concluded that CA exerts an antioxidant action inside the cell. Due to its presence in the diet, therefore, CA may play a role in the modulation of oxidative processes in vivo. In fact, dietary supplementation of CA in rats resulted in a statistically significant increase of alpha-tocopherol both in plasma and lipoprotein (Nardini et al., 1997). While CA was not detectable in plasma under fasting conditions, in postprandial plasma it was present at ^mol concentrations, doubling plasma total antioxidant capacity, and lipoproteins from CA-fed rats were more resistant than control to Cu2+-catalyzed oxidation, despite the lack of incorporation of CA in the particles (Nardini et al., 1997).
Additionally, CA is a selective, non-competitive inhibitor for 5-lipoxygenase and therefore for leukotriene biosynthesis (Koshihara et al., 1984). CA and its methyl ester did not inhibit prostaglandin synthase activity at all, but rather stimulate it at higher doses. The biosynthesis of leukotrienes in mouse mast tumor cells was also inhibited completely with CA. Further, platelet aggregation induced by arachidonic acid was inhibited by CA at high doses, while platelet aggregation induced by ADP is not influenced by CA at all (Koshihara et al., 1984).
Apart from this, CA exerts anti-proliferative effects, as it inhibited T-lymphocyte progenitor cells, particularly at lower cell concentrations, an effect which is restored by leukotriene B4, IL-1 and IL-2 (Miller et al., 1989), and altered the colony-forming ability of MCF-7 human breast carcinoma cells (Ahm et al., 1997). CA markedly reduced the IC50 of doxorubicin (Dox) in multidrug-resistant MCF-7/Dox cells (Ahn et al., 1997). The level of TGF-^1 in MCF-7/Dox cells was about 3-fold greater than that in MCF-7 cells. In cells pretreated with CA, TGF-^1 and TGF-^2 levels were overexpressed only in MCF-7/Dox cells. These results suggest that CA is potentially a chemosensitizing agent with greater selectivity to drug-resistant MCF-7/Dox cells over parent MCF-7 cells and that the chemosensitizing effect is not mediated by altered drug concentrations in the cells, but may be possibly correlated to the induction of TGF-£ isotypes (Ahn et al., 1997).
Topical application of phenolic acids, such as p-coumaric, caffeic, ferulic, gentisic, protocatechuic, syringic and isovanillic acids, was effective against 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear oedema (Fernández et al., 1998). Their action is markedly influenced by the inhibition of neutrophil migration into inflamed tissue (Fernández et al., 1998). While the topical application of curcumin together with TPA inhibited the stimulation of [3H]-thymidine uptake into epidermal DNA, CA, FA and chlorogenic acid were less effective as inhibitors of the TPA-dependent stimulation of DNA synthesis (Huang et al., 1988). However, topical application of curcumin, CA, FA and chlorogenic acid together with TPA twice weekly for 20 weeks to mice previously initiated with 7,12-dimethyl benz(a)anthracene (DMBA) inhibited the number of TPA-induced tumors per mouse (Huang et al., 1988).
Reports on the suggested anti-mutagenic and anti-carcinogenic effects of phenolic compounds are conflicting. Ellagic acid, CA, FA, chlorogenic acid and other phenolic compounds such as purpurogallin, quercetin, alizarin and monolactone were reported to inhibit GSH-transferase(s) activity (Das et al., 1984). In a bacterial mutation assay using Salmonella typhimurium, CA and its derivative chlorogenic acid had inhibitory effects on the mutagenicity of Trp-P-1 and Glu-P-2 (Yamada and Tomita, 1996). CA completely eliminated the mutagenicity induced by activated Glu-P-2. Some compounds analogous to CA, such as cinnamic acid, coumaric acid, and FA, also significantly decreased the mutagenicity of Glu-P-2 (Yamada and Tomita, 1996). In other experiments, polyphenolic acids such as CA, FA, chlorogenic acid and ellagic acid failed to have such an effect in the S. typhimurium strain TA98 as indicator and hepatic S9 mixes as metabolic activating systems, while the plant flavonoids morin, myricetin and quercetin generally inhibited IQ, MelQ, MelQx and Trp-P-1 induced mutagenesis in a dose-dependent manner (Alldrick et al., 1986). Using Chinese hamster ovary (CHO K-1) cells, addition of CA and FA significantly increased the frequency of mitomycin C- and UV-induced DNA lesions, as measured by SCE, while X-ray-induced DNA lesions decreased (Sasaki et al., 1989).
Preliminary experiments of our group revealed a significant induction of SCE in 72 h cultured human whole blood cells by the addition of caffeic acid at 0.1 ^M (from 3.73±1.94 to 6.04±1.83, p>0.001; Büssing et al., in preparation) Further, genotoxicity of DMBA in B6C3F1 mice was protected by CA, as measured by a 50% decrease of the DMBA-induced micronuclei (Raj et al., 1983). Also, topical application of CA and FA simultaneously with phorbol-12-myristate-13-acetate (PMA) or mezerein resulted in significant protection against DMBA-induced skin tumors in mice (Kaul and Khanduja, 1998). As in rats receiving aminopyrine and nitrite, elevation of serum N-nitrosodimethylamine levels and the serum glutamic pyruvic transaminase levels associated with hepatotoxicity were blocked by these phenolic acids, dietary CA and FA may play a role in the body's defense against carcinogenesis by inhibiting the formation of N-nitroso compounds (Kuenzig et al., 1984).
On the other hand, dietary levels of antioxidants such as the butylated hydroxyanisole, CA, sesamol, 4-methoxyphenol and catechol, known to enhance the inci-dences of forestomach papillomas and squamous cell carcinomas in F344 rats treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) (Hirose et al., 1987, 1992), slightly increased the incidences of forestomach papillomas, and significantly increased with the antioxidants in combination (Hirose et al., 1998). However, glandular stomach carcinogenesis was not enhanced (Hirose et al., 1987, 1992). With regard to other organs, the incidence of colon tumors was significantly decreased only in the high dose combination group (Hirose et al., 1998).
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