Conformations of stereoisomeric base adducts to 4-Hydroxyequilenin

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

Research output: Contribution to journalArticle

Abstract

Exposure to estrogen through estrogen replacement therapy increases the risk of women developing cancer in hormone sensitive tissues. Premarin (Wyeth), which has been the most frequent choice for estrogen replacement therapy in the United States, contains the equine estrogens equilin and equilenin as major components. 4-Hydroxyequilenin (4-OHEN) is a phase I metabolite of both of these substances. This catechol estrogen autoxidizes to potent cytotoxic quinoids that can react with dG, dA, and dC to form unusual stereoisomeric cyclic adducts (Bolton, J. L., et al. (1998) Chem. Res. Toxicol. 11, 1113-1127). Like other bulky DNA adducts, these lesions may exhibit different susceptibilities to DNA repair and mutagenic potential, if not repaired in a structure-dependent manner. To ultimately gain insights into structure-function relationships, we computed conformations of stereoisomeric guanine, adenine, and cytosine base adducts using density functional theory. We find near mirror image conformations in stereoisomer adduct pairs for each modified base, suggesting opposite orientations with respect to the 5′ - 3′ direction of the modified strand when the stereoisomer pairs are incorporated into duplex DNA. Such opposite orientations could cause stereoisomer pairs of lesions to respond differently to DNA replication and repair enzymes.

Original languageEnglish (US)
Pages (from-to)695-707
Number of pages13
JournalChemical Research in Toxicology
Volume16
Issue number6
StatePublished - Jun 1 2003

Fingerprint

Stereoisomerism
Conformations
Estrogens
Estrogen Replacement Therapy
Equilenin
Equilin
Catechol Estrogens
DNA Repair Enzymes
Conjugated (USP) Estrogens
DNA
Repair
DNA Adducts
Cytosine
Guanine
Adenine
DNA Replication
DNA Repair
Horses
Metabolites
Hormones

ASJC Scopus subject areas

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

Cite this

Conformations of stereoisomeric base adducts to 4-Hydroxyequilenin. / Ding, Shuang; Shapiro, Robert; Geacintov, Nicholas E.; Broyde, Suse.

In: Chemical Research in Toxicology, Vol. 16, No. 6, 01.06.2003, p. 695-707.

Research output: Contribution to journalArticle

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