The effects of pretreatment with 7,8-benzoflavone on drug-metabolizing enzymes and diethylstilboestrol metabolism in male hamster liver microsomal preparations

Abstract

1. Pretreatment of male Syrian golden hamsters with 7,8-benzoflavone (7,8-BF, 0˙4^% in the diet) for 4 and 20 weeks resulted in a significant increase in the amount of cytochrome P-450 and cytochrome b₅ in hepatic microsomes. The activities of microsomal 7-ethoxycoumarin-O-deethylase (ECOD) and 7-ethoxyresorufin-O-deethylase (EROD) increased by a factor of 2 and 5, respectively, whereas aryl hydrocarbon hydroxylase (AHH) activity was only marginally enhanced.

2. Because the relative increase in cytochrome b₅ exceeded that of cytochrome P-450, the ratio of P-450 to b₅ decreased from 2˙2 in controls to 1˙6 in 7,8-BF-treated animals.

3. Hepatic microsomes from untreated and 7,8-BF-pretreated hamsters metabolize E-diethylstilboestrol (E-DES) to its stereoisomer Z-DES and to several oxidative metabolites, of which 3-hydroxy-DES and Z,Z-dienestrol were unambiguously identified by g.l.c.-mass spectrometry.

4. Pretreatment with 7,8-BF led to a marked decrease in the formation of all oxidative DES metabolites but not in the isomerization to Z-DES. The possible implication of these data for the mechanism of liver tumour formation by the combined treatment of hamsters with 7,8-BF and DES is discussed.