Equilin and equilenin, components of the hormone replacement therapy drug Premarin, can be metabolized to the catechol 4-hydroxyequilenin (4-OHEN). The quinoids produced by 4-OHEN oxidation react with dC, dA, and dG to form unusual stable cyclic adducts, which have been found in human breast tumor tissue. Four stereoisomeric adducts have been identified for each base. These 12 Premarin-derived adducts provide a unique opportunity for analyzing effects of stereochemistry and base damage on DNA structure and consequently its function. Our computational studies have shown that these adducts, with obstructed Watson-Crick hydrogen-bond edges and near-perpendicular ring systems, have limited conformational flexibility and near-mirror-image conformations in stereoisomer pairs. The dC and dA adducts can adopt major- and minor-groove positions in the double helix, but the dG adducts are positioned only in the major groove. In all cases, opposite orientations of the equilenin rings with respect to the 5′ → 3′ direction of the damaged strand are found in stereoisomer pairs derived from the same base, and no Watson-Crick pairing is possible. However, detailed structural properties in DNA duplexes are distinct for each stereoisomer of each damaged base. These differences may underlie observed differential stereoisomer and base-dependent mutagenicities and repair susceptibilities of these adducts.
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