Synthesis and reactivity of potential carcinogenic catechol metabolites from equine estrogens and tamoxifen.

摘要

Equilin, equilenin, and 8,9-dehydroestrone make up approximately 50% of Premarin® which is currently the most popular drug formulation for estrogen replacement therapy. Although there are numerous health benefits of estrogen replacement therapy, there is a clear association between excessive exposure to estrogens and the development of cancer in several tissues including breast and endometrium. One potential mechanism of estrogen carcinogenesis involves metabolism of estrogens to 2- and 4-hydroxylated catechols that are further oxidized to electrophilic/redox active o-quinones, which have the potential to both initiate and promote the carcinogenic process. In the present study, we synthesized catechol metabolites of equilin, equilenin, and 8,9-dehydroestrone. They included 4-hydroxyequilin, 2-hydroxyequilin, 4-hydroxyequilenin, 2-hydroxyequilenin, 4-hydroxy-8,9-dehydroestrone, and 2-hydroxy-8,9-dehydroestrone. The reactivity of these catechols with GSH, deoxnucleosides, and DNA was studied. The metabolism of these equine estrogens in rat liver microsomes were also investigated. Preliminary results showed that almost all of these catechols (except 2-hydroxyequilenin) formed GSH conjugatesand 4-hydroxyequilin was found to react with deoxynucleosides and DNA to form very unusual cyclic adducts. These data might support the link between long-term estrogen replacement therapy and the enhanced risk of breast cancer through the catechol carcinogenic mechanism.; Although tamoxifen is approved for the treatment of hormone-dependent breast cancer as well as prevention of breast cancer in high-risk women, several studies in animal models have shown that tamoxifen is heptocarcinogenic and in humans tamoxifen has been associated with an increased risk of endometrial cancer. One potential mechanism of tamoxifen carcinogenesis involves metabolism of tamoxifen to 3,4-dihydroxytamoxifen followed by oxidation to a highly reactive o-quinone that has the potential to alkylate/oxidize cellular macromolecules in vivo. In the present study, we synthesized 3,4-dihydroxytamoxifen, prepared its o-quinone chemically and enzymatically, and studied the reactivity of the o-quinone with GSH and deoxynucleosides. These experimental results suggest that the catechol metabolite of tamoxifen has the potential to cause cytotoxicity in vivo through formation of 3,4-dihydroxytamoxifen o-quinone.