Role of Prostaglandin-H Synthase in Mediating Genotoxic and Carcinogenic Effects of Estrogens

Abstract

Diethylstilbestrol (DES) has been found to be oxidized in Syrian hamster embryo (SHE) cells by prostaglandin-H synthase (PGH synthase). It is hypothesized that PGH synthase mediates adverse effects of DES and other carcinogenic estrogens such as induction of neoplastic transformation and genotoxicity. Interest in PGH synthase-catalyzed reactions focuses on two aspects: oxidation and metabolic activation of stilbene and steroid estrogens by PGH synthase, and modulation of prostaglandin biosynthesis via effects of these compounds on PGH synthase. Studies of the former aspect of PGH synthase-catalyzed in vitro metabolism have revealed that cooxidation of DES, DES analogues, and steroid estrogens gives rise to reactive intermediates; DES and DES analogues known to transform SHE cells are metabolized by PGH synthase in vitro; PGH synthase catalyzes both the formation and oxidation of catechol metabolites from steroid estrogens, and reactive intermediates from DES and from steroid estrogens are stable enough to bind both to the catalytic enzyme PGH synthase and to other proteins. The data support the contention that PGH synthase-catalyzed metabolic activation plays a role in the induction of neoplastic transformation by stilbene and steroid estrogens but is not conclusive evidence for a cause-effect relationship. More recently, two closely related DES indanyl analogues have been found to differ in their interaction with PGH synthase: indenestrol A is cooxidized and activated like DES, whereas indenestrol B inhibits the enzyme. They provide useful tools to test the above hypothesis from a new perspective.(ABSTRACT TRUNCATED AT 250 WORDS)