文摘
The risk factors for women developing breast and endometrial cancers are all associatedwith a lifetime of estrogen exposure. Estrogen replacement therapy in particular has beencorrelated with an increased cancer risk. Previously, we showed that the equine estrogensequilin and equilenin, which are major components of the widely prescribed estrogenreplacement formulation Premarin, are metabolized to highly cytotoxic quinoids which causedoxidative stress and alkylation of DNA in vitro [Bolton, J. L., Pisha, E., Zhang, F., and Qiu, S.Chem. Res. Toxicol. 1998, 11, 1113-1127]. In this study, we have synthesized 8,9-dehydroestrone (a third equine estrogen component of Premarin) and its potential catecholmetabolites, 4-hydroxy-8,9-dehydroestrone and 2-hydroxy-8,9-dehydroestrone. Both 2-hydroxy-8,9-dehydroestrone and 4-hydroxy-8,9-dehydroestrone were oxidized by tyrosinase or rat livermicrosomes to o-quinones which reacted with GSH to give one mono-GSH conjugate and twodi-GSH conjugates. Like endogenous estrogens, 8,9-dehydroestrone was primarily convertedby rat liver microsomes to the 2-hydroxylated rather than the 4-hydroxylated o-quinone GSHconjugates; the ratio of 2-hydroxy-8,9-dehydroestrone versus 4-hydroxy-8,9-dehydroestrone was6:1. Also in contrast to experiments with equilin, 4-hydroxyequilenin was not observed inmicrosomal incubations with 8,9-dehydroestrone or its catechols. The behavior of 2-hydroxy-8,9-dehydroestrone was found to be more complex than 4-hydroxy-8,9-dehydroestrone as GSHconjugates resulting from 2-hydroxy-8,9-dehydroestrone were detected even without oxidativeenzyme catalysis. Under physiological conditions, 2-hydroxy-8,9-dehydroestrone isomerized to2-hydroxyequilenin to form the very stable 2-hydroxyequilenin catechol; however, 4-hydroxy-8,9-dehydroestrone was found to be stable under similar conditions. Finally, preliminary studiesconducted with the human breast tumor S-30 cell lines demonstrated that the catecholmetabolites of 8,9-dehydroestrone were much less toxic than 4-hydroxyequilenin (20-40-fold).These results suggest that the catechol metabolites of 8,9-dehydroestrone may have the abilityto cause cytotoxicity in vivo primarily through formation of o-quinones; however, most of theadverse effects of Premarin estrogens are likely due to formation of 4-hydroxyequilenino-quinone from equilin and equilenin.
