Phytoestrogens

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More than 300 plants are known to contain compounds exhibiting estrogenic activity [26]. Typical examples of such phytoestrogens are the isoflavones GEN and daidzein (DAI, Fig. 4), prominent in soy beans, the coumestan COM, present in sprouts of soy beans and alfalfa, and lignans, present in oilseeds, vegetables, and fruit. The two major plant lignans, secoisolariciresinol (SEC) and matairesinol (MAT, Fig. 4), are metabolized by intestinal bacteria to the mammalian lignans enterodiol (END) and enterolactone (ENL). Depending on the diet, some phytoestrogens may be ingested in considerable amounts, e.g., GEN and DAI with soy-based food and SEC and MAT with food containing flaxseed, and lead to plasma levels in the micromolar range [27]. Recently, isoflavones and lignans have gained interest due to their putative beneficial health effects. Consequently, there is an increasing tendency to consume phytoestrogens as dietary supplements.

Despite their widespread occurrence and dietary consumption, as well as their structural similarity with carcinogenic estrogens like DES and E2, very little is known about the genotoxic potential of phytoestrogens and their metabolites. The results of recent studies on the effects of several prominent phyto-estrogens in cultured Chinese hamster V79 cells at various endpoints of genetic damage, e.g., induction of micronuclei, interference with cytoplasmic and mitotic microtubules, and mutations at the hprt gene locus [28,29], are summa-

Table 1. Genotoxic effects of various phytoestrogens in cultured V79 cells, according to [28] and [29]

Effect GEN DAI COM END ENL SEC MAT

Table 1. Genotoxic effects of various phytoestrogens in cultured V79 cells, according to [28] and [29]

Effect GEN DAI COM END ENL SEC MAT

Induction of micronuclei

CREST-positive CREST-negative

+++ -

++ - - - -

Interference with MT

Disruption of CMTC Mitotic spindle Cell-free MT assembly

- -

- - - - -

Induction of mitotic arrest

- -

-----

Mutations at hprt locus

(+)

++ - - - -

rized in Table 1. A clearly distinct genotoxic profile was obtained for the seven phytoestrogens: whereas the four lignans and DAI did not show an effect at any of the endpoints, the induction of micronuclei containing acentric chromosomal fragments (as tested with the antikinetochore CREST antibody) and gene mutations at the hprt locus were observed for GEN and COM. GEN also proved mutagenic in human lymphoblastoid cells [30] and caused DNA strand breaks in the human colon tumor cell line HT29 [31]. The clastogenicity of GEN and COM, but not DAI, was also clearly demonstrated in cultured human peripheral blood lymphocytes [32]. It should be noted that GEN and DAI differ by just one hydroxyl group (Fig. 4), indicating that the genotoxicity is closely associated with the chemical structure. The specificity of the genotoxic effect is also illustrated by comparing COM with the structurally similar DES (Fig. 1): whereas COM is a clastogen and gene mutagen in V79 cells without any aneuploidogenic potential, DES is a clear aneugen in the same cells without any clastogenicity (see Sect. 3.2).

The biological significance of the clastogenicity and mutagenicity of GEN remains to be studied. With the exception of a recent report associating leukemia in Japanese infants with a soy diet [33], no epidemiological studies appear to exist linking isoflavones to increased cancer incidence in humans. A long-term carcinogenicity study in rodents is currently being conducted by the National Toxicology Program. In neonatal CD-1 mice, an animal model used to demonstrate the carcinogenicity of E2 (see Sect. 2.1.1) and DES (see Sect. 3.2), GEN induced the same incidence (about 30%) of uterine adenocarcinoma as did DES when administered at an equiestrogenic dose [34]. However, it is still unclear whether genotoxicity plays a role in the mechanism of estrogen carcinogenesis in this animal model.

In addition to the parent phytoestrogens, their metabolites, in particular hy-droxylation products, may contribute to a possible genotoxic risk. At present, however, no data exist on the genotoxic potential of phase I or phase II metabolites of isoflavones and lignans. Surprisingly little was known until recently about the phase I metabolism of prominent phytoestrogens in humans and ex-

Table 2. Oxidative metabolites of GEN, DAI, END and ENL identified in human urine after ingestion of soy and flaxseed, according to [36] and [40]. HO, hydroxy; position of HO- see Fig. 4. The sequence of listing does not reflect the amount of the respective metabolite

Phyto- Metabolites estrogen

GEN 6-HO-GEN, 8-HO-GEN, 3'-HO-GEN, 3',6-diHO-GEN, 3',8-diHO-GEN

DAI 6-HO-DAI, 8-HO-DAI, 3'-HO-DAI, 6,8-diHO-DAI, 3',6-diHO-DAI, 3',8-diHO-DAI

ENL 2-HO-ENL, 4-HO-ENL, 6-HO-ENL, 2'-HO-ENL, 4'-HO-ENL, 6'-HO-ENL

perimental animals other than the biotransformation by intestinal bacteria. However, both isoflavones and lignans appear to be substrates for mammalian cytochrome P450, as rat and human hepatic microsomes are capable of generating several hydroxylated metabolites of DAI and GEN [35-38], and of END and ENL [39]. Most of these oxidative in vitro metabolites have also been detected in the urine of humans after ingestion of a diet containing soy or flaxseed (Table 2). All of the GEN and DAI metabolites are catechols, whereas the major metabolites of END and ENL are hydroquinones. It should prove interesting to examine the genotoxic potential of these metabolites.

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