Conformational properties of equilenin - DNA adducts: Stereoisomer and base effects

Shuang Ding, Robert Shapiro, Yuqin Cai, Nicholas E. Geacintov, Suse Broyde

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1064-1073
Number of pages10
JournalChemical Research in Toxicology
Volume21
Issue number5
DOIs
StatePublished - May 2008

Fingerprint

Equilenin
Stereoisomerism
DNA Adducts
Conjugated (USP) Estrogens
Equilin
Drug therapy
Stereochemistry
DNA
Hormone Replacement Therapy
DNA Damage
Conformations
Structural properties
Tumors
Hydrogen
Hydrogen bonds
Mirrors
Repair
Hormones
Tissue
Breast Neoplasms

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Conformational properties of equilenin - DNA adducts : Stereoisomer and base effects. / Ding, Shuang; Shapiro, Robert; Cai, Yuqin; Geacintov, Nicholas E.; Broyde, Suse.

In: Chemical Research in Toxicology, Vol. 21, No. 5, 05.2008, p. 1064-1073.

Research output: Contribution to journalArticle

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