SOYBEAN ISOFLAVONE EXTRACT SUPPRESSES EARLY BUT NOT LATER PROMOTION OF HEPATOCARCINOGENESIS BY PHENOBARBITAL IN FEMALE RAT-LIVER

The antioxidant and anticarcinogenic activities of soybean isoflavone extracts were investigated in female F344/N rats. Diethylnitrosamine (DEN, 15 mg/kg body wt) as a cancer initiator was injected intraperitoneally into 120 female F344/N rats at 10 days of age, and at weaning, phenobarbital (PB, 500 mg/kg diet) was fed to one-half of the rats. Soybean isoflavones were extracted in acetone-0.1 N HCl and analyzed by high-performance liquid chromatography, and two levels of soybean isoflavones (920 and 1,840 mu mol/kg diet) were fed during PB treatment for 3 and 11 months. Control rats were fed diets without PB and with or without isoflavones. The effect of soybean isoflavone extract on hepatic glutathione peroxidase was measured, and development of gamma-glutamyltransferase (GGT)-positive (GGT(+)) and placental glutathione transferase (PGST)-positive (PGST(+)) altered hepatic foci (AHF) was analyzed by computerized stereology. Soybean isoflavone extract providing 920 or 1,840 mu mol/kg diet normalized total hepatic glutathione peroxidase activity, which was suppressed about 17% by PB (p < 0.05), and both doses of isoflavone extract suppressed PB promotion of hepatocarcinogenesis, decreasing the volume occupied by GGT(+) and PGST(+) AHF (p < 0.05) after three months. After 11 months of PB promotion, isoflavone extract at 920 mu mol/kg diet decreased PGST(+) AHF compared with the PB-fed group, but neither dose of isoflavone extract suppressed development of GGT(+) AHF compared with the group fed PB alone. Furthermore the control group fed isoflavone extract at 1,840 mu mol/kg diet showed greater development of GGT(+) and PGST(+) AHF than the group fed the basal diet alone. Therefore soybean isoflavones may be anticarcinogenic, but their margin of safety is relatively narrow with a cancer-promoting dose of 1,840 mu mol/kg in female F344/N rats initiated with DEN.