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 intraperiton eally into 120 female F344/N rats at 10 days of age, and at weaning, p henobarbital (PB, 500 mg/kg diet) was fed to one-half of the rats. Soy bean isoflavones were extracted in acetone-0.1 N HCl and analyzed by h igh-performance liquid chromatography, and two levels of soybean isofl avones (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 w ithout isoflavones. The effect of soybean isoflavone extract on hepati c glutathione peroxidase was measured, and development of gamma-glutam yltransferase (GGT)-positive (GGT(+)) and placental glutathione transf erase (PGST)-positive (PGST(+)) altered hepatic foci (AHF) was analyze d by computerized stereology. Soybean isoflavone extract providing 920 or 1,840 mu mol/kg diet normalized total hepatic glutathione peroxida se activity, which was suppressed about 17% by PB (p < 0.05), and both doses of isoflavone extract suppressed PB promotion of hepatocarcinog enesis, 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 develo pment of GGT(+) AHF compared with the group fed PB alone. Furthermore the control group fed isoflavone extract at 1,840 mu mol/kg diet showe d greater development of GGT(+) and PGST(+) AHF than the group fed the basal diet alone. Therefore soybean isoflavones may be anticarcinogen ic, but their margin of safety is relatively narrow with a cancer-prom oting dose of 1,840 mu mol/kg in female F344/N rats initiated with DEN .