4-hydroxyequilenin-adenine lesions in DNA duplexes: stereochemistry, damage site, and structure.
The equine estrogens, equilin and equilenin, are major components of the drug Premarin, the most widely used formula for hormone replacement therapy. The derivative 4-hydroxyequilenin (4-OHEN), a major phase I metabolite of equilin and equilenin, autoxidizes to potent cytotoxic quinoids that can react in vitro and in vivo with cytosine and adenine in DNA. Unique cyclic adducts containing the same bicyclo[3.3.1]nonane-type connection ring are produced. Each base adduct has four stereoisomers. In order to elucidate the structural effects of A versus C modification, we have carried out molecular dynamics simulations of the stereoisomeric 4-OHEN-A adducts in DNA 11-mer duplexes and compared results with an earlier study of the C adducts (Ding, S., Shapiro, R., Geacintov, N.E., and Broyde, S. (2005) Equilenin-Derived DNA Adducts to Cytosine in DNA Duplexes: Structures and Thermodynamics, Biochemistry 44, 14565-14576). Similar stereochemical principles govern the orientations in DNA duplexes of the 4-OHEN-A adducts as for the analogous C adducts, with opposite orientations of the equilenin rings in stereoisomeric pairs of adducts characterized by near-mirror image circular dichroism (CD) spectra. However, the larger purine adducts have unique structural properties in the duplexes that distinguish their characteristics from those of the pyrimidine adducts. Significant differences are observed in terms of hydrogen bonding, stacking, bending, groove dimensions, solvent exposure, and hydrophobic interactions; also, each of the four stereoisomeric 4-OHEN-A adducts exhibit distinct structural features. Each base adduct and stereoisomer distorts the structure of the DNA duplex differently. These characteristics may manifest themselves in terms of differential nucleotide excision repair susceptibilities and mutagenic activities of the 4-OHEN-A and C adducts.
Ding
Shuang
S
Department of Chemistry and Department of Biology, New York University, 100 Washington Square East, New York, New York 10003.
Shapiro
Robert
R
Geacintov
Nicholas E
NE
Broyde
Suse
S
D000225:Adenine / Q000737:chemistry*; D004247:DNA / Q000737:chemistry*; D018736:DNA Adducts / Q000737:chemistry*; D004249:DNA Damage; D004855:Equilenin / Q000031:analogs & derivatives* / Q000737:chemistry; D006860:Hydrogen Bonding; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D018736:DNA Adducts; C065250:4-hydroxy-equilenin; D004247:DNA; D000225:Adenine; D004855:Equilenin