Flavonoids and Phenylpropanoids

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Flavonoids such as quercetin and its derivatives are diphenyl propanoids widely distributed in dietary plants, and also present in Viscum album (see Becker, this book). They are suggested to play a dual role in mutagenesis and carcinogenesis. In fact, quercetin was recognized to induce apoptosis in various malignant and non-malignant cell lines (Wei et al, 1994; Kuo, 1996; Plaumann et al., 1996; Fujita et al, 1997; Csokay et al., 1997; Weber et al., 1997), but also to exert mutagenic properties, as measured by mutagenicity assays such as Ames test, Comet assay, micronucleus test, and DNA fingerprint analysis (Hardigree and Epler, 1978; MacGregor and Jurd, 1978; Sahu et al., 1981; Hatcher and Bryan, 1985; Rueff et al., 1986; Malinowski et al., 1990; Suzuki et al., 1991; Anderson et al., 1997). Indeed, quercetin induced both, SCE-inducing DNA lesions in cultured peripheral blood mononuclear cells and apoptosis, while the phenylpropanoid syringin induced SCE only at higher but less cytotoxic concentrations (Figure 5). Thus, both phenomenons are different end-points of cellular affection by these compounds. However, quercetin may also act as an protectant against hydrogen peroxide-induced DNA strand breaks (Duthie et al., 1997).

Although quercetin is highly mutagenic in vitro, it is not necessarily carcinogenic when administered in vivo. While quercetin was found to induce micronuclei in vitro in V79 cells and human lymphocytes, it failed to induce them in vivo, as measured in bone marrow polychromatic erythrocytes in mice (Caria et al., 1995). In fact, chronical application of high doses (50 mg/kg BW) to rodents for 12 month was not carcinogenic, an effect which was shown to be dependent on the rapid metabolic inactivation of the flavonoid by catechol-o-methytransferase (Zhu et al., 1994). Also, no tumour or hyperplasia were observed in F344 rats fed with 5% quercetin in the diet for 4 weeks followed by N-butyl-N-(4-hydroxybutyl) nitrosamine for 29 weeks, and no lesions were detected in rats given 5% quercetin diet only (Hirose et al., 1983), indicating that the flavonoid is not carcinogenic in rat urinary bladder. On the other hand, in F344/N rats fed with quercetin (about 40 to 1,900 mg/kg BW/d) for 2 years, toxic and neoplastic lesions were seen in the kidney, including increased severity of chronic nephrophathy, hyperplasia, and benign tumours of the renal tubular epithelium (Dunnick and Hailey, 1992). In the nitrosomethylurea (NMU) model of rat pancreatic carcinogenesis, quercetin was recognized to exert a promoting and progressing effect: dietary quercetin in rats treated with NMU resulted in a significantly higher number of rats with dysplastic foci (pancreatic nodules and focal acinar cell hyperplasias) (Barotto et al., 1998). Furthermore, carcinoma in situ and one microcarcinoma were found in these animals. Mitosis was significantly increased and apoptosis was diminished in focal acinar cell hyperplasias of the quercetin group (Barotto et al., 1998). Zhu and Liehr (1994) observed an increase of estradiol-induced tumourigenesis in Syrian hamsters by the coadministration of estradiol plus 3% quercetin, i.e. increased number of tumour nodules and incidence of abdominal metastases. Also Ishikawa et al. (1985) reported an enhancing effect of quercetin on 3-methylcholanthrene carcinogenesis in C57B1/6 mice, an effect suggested to be associated with an increased mutation rate in the host.

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