Prostaglandin-H-Synthase Catalyzed Formation of Reactive Intermediates from Stilbene and Steroid Estrogens: Covalent Binding to Proteins
DES, a well known carcinogen in humans, as well as certain of its structural analogs and steroid estrogens are carcinogenic in animals and have been found to exert genotoxic effects in short term assays. In some model systems the adverse effect is not strictly related to estrogenicity, and e.g., induction of UDS or SCE by DES apparently requires its oxidative metabolism (Degen and Metzler 1987). In estrogen target tissues and in Syrian hamster embryo (SHE-)cells which are neoplastically transformed by DES and related compounds, prostaglandin- H-synthase (PHS) is found. PHS has both cyclooxygenase and peroxidase activity, and during in vitro conversion of arachidonic acid (AA) it can oxidize a number of substrates; this reaction termed “cooxidation” (Marnett and Eling 1983) makes PHS a candidate enzyme for metabolic activation. Radiolabeled DES and other estrogens when incubated with ram seminal vesical microsomes, a rich source of PHS, have been found to be cooxidized in part to nonextractable metabolites bound to microsomal protein (Degen 1985; Degen et al 1985 and 1985). This study aims to investigate further the nature of this binding as well as reactivity and stability of various estrogen intermediates.
KeywordsArachidonic Acid Covalent Binding Steroid Estrogen Hamster Embryo Cell Syrian Hamster Embryo
bovine serum albumin
sister chromatid exchange
Syrian hamster embryo fibroblasts
Unable to display preview. Download preview PDF.
- Degen GH (1985) Prostaglandin synthase catalyzed metabolism of synthetic and steroidal estrogens. In: Siest G (ed) Drug metabolism: molecular approaches and pharmacological implications. Pergamon Press, Oxford, pp 223–228Google Scholar
- Degen GH, Metzler M (1985) Metabolic activation of hexestrol, a structural analog of the carcinogen diethylstilbestrol by prostaglandinsynthase. J Cancer Res Clinic Oncol 109: A 13Google Scholar
- Freyberger A, Degen GH (1989) Covalent binding of reactive intermediates resulting from prostaglandin H synthase catalyzed oxidation of stilbene- and steroid estrogens. J Biochem Toxicol (in press)Google Scholar
- Marnett LJ, Eling TE (1983) Cooxidation during prostaglandin biosynthesis: a pathway for the metabolic activation of xenobiotics. Rev Biochem Toxicol 5: 135–172Google Scholar