Prostaglandin-H-Synthase Catalyzed Formation of Reactive Intermediates from Stilbene and Steroid Estrogens: Covalent Binding to Proteins

  • A. Freyberger
  • G. H. Degen
Part of the Archives of Toxicology book series (TOXICOLOGY, volume 13)


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.


Arachidonic Acid Covalent Binding Steroid Estrogen Hamster Embryo Cell Syrian Hamster Embryo 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.





bovine serum albumin


arachidonic acid












unscheduled DNA-synthesis


sister chromatid exchange


Syrian hamster embryo fibroblasts


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 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
  2. 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
  3. Degen GH, Metzler M (1987) Sex hormones and neplasia: genotoxic effects in short term assays. Arch Toxicol Suppl 10: 264–278PubMedCrossRefGoogle Scholar
  4. Degen GH, Metzler M, Sivarajah KS (1986) Co-oxidation of diethylstilbestrol and structural analogs by prostaglandin synthase. Carcinogenesis 7: 137–142PubMedCrossRefGoogle Scholar
  5. Degen GH, Hershcopf RJ, Hellinck PH (1987) Regiospecific release of tritium water from estradiol catalyzed by prostaglandin synthase-peroxidase. Steroids 49: 561–580PubMedCrossRefGoogle Scholar
  6. Epe B, Hegler J, Metzler M (1987) Site-specific covalent binding of stilbene-type and steroidal estrogens to tubulin following metabolic activation in vitro. Carcinogenesis 8: 1271–1275PubMedCrossRefGoogle Scholar
  7. 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
  8. Marnett LJ, Eling TE (1983) Cooxidation during prostaglandin biosynthesis: a pathway for the metabolic activation of xenobiotics. Rev Biochem Toxicol 5: 135–172Google Scholar
  9. Numazawa M, Kiyono Y, Nambara T (1980) A simple radiometric assay for estradiol 2-hydroxylase activity. Anal Biochem 104: 290–295PubMedCrossRefGoogle Scholar
  10. Tsutsui T, Suzuki N, Fukuda S, Sato M, Maizumi H, McLachlan JA, Barrett JC (1987) 17β-estradiol-induced cell transformation and aneuploidy of Syrian hamster embryo cells in culture. Carcinogenesis 8: 1715–1719PubMedCrossRefGoogle Scholar
  11. Yamazoe Y, Miller DW, Weis CC, Dooley KL, Zenser TV, Beland FA, Kadlubar FF (1985) DNA adducts formed by ring-oxidation of the carcinogen 2-naphthylamine with prostaglandin H synthase in vitro and in the dog urothelium in vivo. Carcinogenesis 6: 1379–1387PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1989

Authors and Affiliations

  • A. Freyberger
    • 1
  • G. H. Degen
    • 1
  1. 1.Institute of Toxicology, SFB 172, University of WürzburgWürzburgFed. Rep. Germany

Personalised recommendations