GENETIC-DAMAGE AND THE INHIBITION OF 7,12-DIMETHYLBENZ[ALPHA]ANTHRACENE-INDUCED GENETIC-DAMAGE BY THE PHYTOESTROGENS, GENISTEIN AND DAIDZEIN, IN FEMALE ICR MICE

Populations consuming soybeans have reduced rates of breast, colon and prostate cancer possibly due, in part, to the presence in soybeans of two estrogenic isoflavones, genistein and daidzein. This study invest igated the genotoxicity of these soya isoflavones and their interactio ns with 7,12-dimethylbenz[a]anthracene (DMBA)-induced sister chromatid exchanges (SCE) in bone marrow cells and DNA adduct formations in liv er and mammary glands of mice. Groups of female ICR mice were pretreat ed i.p. with daidzein and/or genistein (10-20 mg/kg per day for 6 days or 50 mg/kg per 12 h for 3 days) or with the solvent, dimethylsulfoxi de (DMSO). The mice were implanted with bromodeoxyuridine (BrdU) table ts s.c., and treated with DMBA (50 mg(kg) i.p. and colchicine (4 mg/kg ) i.p. 24, 23, and 2 h before sacrifice, respectively, In bone marrow cells, DMBA alone induced 11.73 +/- 1.42 SCE/cell compared to 4.35 +/- 0.83 SCE/cell in the DMSO treated controls (P = 0.001). DMBA induced 20% fewer SCE (P < 0.05) in mice pretreated with daidzein, genistein o r a combination of genistein and daidzein (6 x 20 mg/kg per day for 6 days) when compared to mice that received no pretreatments. Genistein at 50 mg/kg per 12 h for 3 days also inhibited DMBA-induced SCE by 20% . However, treatment for 3 days with 50 mg/kg per 12 h of genistein or daidzein alone, or a combination of daidzein plus genistein (without DMBA treatment) also induced more SCE than treatment with only the sol vent (DMSO, P < 0.05). Pretreatment with both the low and the high dos es of daidzein plus genistein or the high dose of genistein reduced th e replication index of bone marrow cells when compared to pretreatment with DMSO (P < 0.05). Pretreatment with genistein reduced DMBA-induce d DNA adduct formation by 34%, but this was only marginally significan t (P = 0.08) due to the large inter-individual variability in adduct l evels. These results show that genistein and daidzein suppress SCE and possibly DNA adduct formation induced by the known carcinogen, DMBA. This response to a low dose isoflavone exposure may be partly responsi ble for the protective effect against endocrine cancers of soya consum ption.