Molecular characteristics of catechol estrogen quinones in reactions with deoxyribonucleosides.
Estrogens can have two roles in the induction of cancer: stimulating proliferation of cells by receptor-mediated processes, and generating electrophilic species that can covalently bind to DNA. The latter role is thought to proceed through catechol estrogen metabolites, which can be oxidized to o-quinones that bind to DNA. Four estrogen-deoxyribonucleoside adducts were synthesized by reaction of estrone 3,4-quinone (E1-3,4-Q), 17 beta-estradiol 3,4-quinone (E2-3,4-Q), or estrone 2,3-quinone (E1-2,3-Q) with deoxyguanosine (dG) or deoxyadenosine (dA) in CH3CO2H/H2O (1:1). Reaction of E1-3,4-Q or E2-3,4-Q with dG produced specifically 7-[4-hydroxyestron-1(alpha, beta)-yl]guanine (4-OHE1-1(alpha, beta)-N7Gua) or 7-[4-hydroxyestradiol-1(alpha, beta)-yl]-guanine (4-OHE2-1(alpha, beta)-N7Gua), respectively, in 40% yield, with loss of deoxyribose. These two quinones did not react with dA, deoxycytidine, or thymidine. When E1-2,3-Q was reacted with dG or dA, N2-(2-hydroxyestron-6-yl)deoxyguanosine (2-OHE1-6-N2dG, 10% yield) and N6-(2-hydroxyestron-6-yl)deoxyadenosine (2-OHE1-6-N6dA, 80% yield), respectively, were formed. These adducts provide insight into the type of DNA damage that can be caused by o-quinones of the catechol estrogens. The estrogen 3,4-quinones are expected to produce depurinating guanine adducts that are lost from DNA, generating apurinic sites, whereas the 2,3-quinones would form stable adducts that remain in DNA, unless repaired. The adducts reported here will be used as references in studies to elucidate the structure of estrogen adducts in biological systems.
Stack
D E
DE
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha 68198-6805, USA.
Byun
J
J
Gross
M L
ML
Rogan
E G
EG
Cavalieri
E L
EL
D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000737:chemistry; D004249:DNA Damage; D003853:Deoxyribonucleosides / Q000737:chemistry*; D002393:Estrogens, Catechol / Q000138:chemical synthesis / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D011809:Quinones / Q000138:chemical synthesis / Q000737:chemistry; D016339:Spectrometry, Mass, Fast Atom Bombardment
D003853:Deoxyribonucleosides; D002393:Estrogens, Catechol; D011809:Quinones; D004247:DNA