Role of metabolic activation in the carcinogenicity of estrogens: studies in an animal liver tumor model.

Male Syrian golden hamsters chronically exposed to certain synthetic estrogens such as diethylstilbestrol (DES) or 17 alpha-ethinylestradiol (EE2) and fed a diet containing 7,8-benzoflavone (BF) develop a high incidence of liver tumors. No such tumors are found in animals treated with estrogen or BF alone. To clarify the role of metabolic activation of the estrogen and BF in the mechanism of hepatocarcinogenesis in this animal model, the effects of pretreatment with DES and EE2 alone and in combination with BF on the metabolism of DES, EE2, and BF in hepatic microsomes, isolated hepatocytes, and hamster bile were studied. Hamsters were pretreated for up to 32 weeks. The results clearly show that DES metabolism was not significantly modified under any pretreatment regimen. EE2 metabolism exhibited a slight increase in 2-hydroxylation after pretreatment with BF and with BF plus EE2. The most pronounced effect was observed in BF metabolism after pretreatment with BF, with BF plus DES, and with BF plus EE2: the metabolic rate was increased and several new metabolites that were not found in untreated or estrogen-pretreated animals were formed. These metabolites were tentatively identified as BF-dihydrodiol and dihydroxy-BFs. The formation of these new BF metabolites was accompanied by a change in the activities of certain cytochrome P-450 isoenzymes in hamster liver microsomes. The results of this study imply that metabolic activation of BF rather than of the estrogens plays an important role in the mechanism of carcinogenesis in this animal liver tumor model.