Effect of pretreatment with 7,8-benzoflavone and diethylstilbestrol on the hepatic metabolism of diethylstilbestrol in the male Syrian golden hamster in vivo.
Liver tumors are induced in male Syrian golden hamsters by the combined treatment with diethylstilbestrol (DES) and 7,8-benzoflavone (7,8-BF), but not with either substance alone. With the aim of clarifying whether metabolic activation of DES is involved in the mechanism of tumorigenesis in this animal model, we have studied the effect of pretreatment with 7,8-BF alone, DES alone, and 7,8-BF plus DES for 2, 8, 20 and 32 weeks on the hepatic in vivo metabolism of DES, using biliary metabolites collected from bile-duct cannulated male hamsters as probe. Formation of glucuronides and sulfates was not affected by treatment with 7,8-BF nor 7,8-BF plus DES. In contrast, animals pretreated with DES alone had a decreased amount of glucuronides and an increased proportion of unconjugated material in the bile. Oxidative metabolism of DES was not significantly altered in hamsters treated with 7,8-BF for up to 20 weeks, whereas pretreatment with DES alone and with 7,8-BF plus DES caused an enhancement of oxidative DES metabolism in vivo, leading mostly to highly polar, as yet unidentified products. From a consideration of various cytochrome P-450-associated enzyme activities, it is concluded that the observed effect on biliary DES metabolites is most likely to be due to an estrogen-induced intrahepatic cholestasis. Taken together, the data do not support a role for the metabolic activation of DES in this tumor model. Alternative mechanisms are proposed.
Blaich
G
G
Institute of Pharmacology and Toxicology, University of Würzburg, Federal Republic of Germany.
Metzler
M
M
D000818:Animals; D001571:Benzoflavones / Q000378:metabolism / Q000494:pharmacology*; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D006224:Cricetinae; D004247:DNA / Q000378:metabolism; D004054:Diethylstilbestrol / Q000378:metabolism* / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008647:Mesocricetus; D010084:Oxidation-Reduction
D001571:Benzoflavones; D005419:Flavonoids; C011512:alpha-naphthoflavone; D004054:Diethylstilbestrol; D004247:DNA