Spectral characterization of fluorescently labeled catechol estrogen 3,4-quinone-derived N7 guanine adducts and their identification in rat mammary gland tissue

Ryszard Jankowiak, Dan Zamzow, Douglas E. Stack, Rosa Todorovic, Ercole L. Cavalier, Gerald J. Small

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

The oxidation of carcinogenic 4-hydroxycatechol estrogens (CE) of estrone (E1) and estradiol (E2) to catechol estrogen 3,4-quinones (CE-3,4- Q) results in electrophilic intermediates that covalently bind to DNA to form depurinating adducts [Cavalieri et al. (1997) Proc. Natl. Acad. Sci. U.S.A. 94, 10937]. These DNA adducts, 4-OHE1-1-N7Gua and 4-OHE2-1-N7Gua, are non fluorescent. To utilize laser-excited fluorescence methods, the catechol estrogen-derived metabolites and adducts were labeled with a fluorescent marker. The 4-OHE1-1-N7Gua adduct standards (i = 1, 2) and 4-OHE1 metabolites have been derivatized with 1-pyrenesulfonyl chloride and investigated by low-temperature spectroscopy under non-line-narrowing and line-narrowing conditions. Molecular modeling studies assisted in interpretation of the fluorescence spectra; energetically favored structures of the 4-OHE2-1-N7Gua-dipyrene adduct and 4-OHE2-dipyrene metabolite reveal unique conformations which, in agreement with fluorescence data, show a significant π-π interaction of pyrene labels with guanine and/or the aromatic ring of catechol estrogen. The conformation obtained for the 4- OHE2-1-N7Gua-dipyrene adduct appears to be conducive to mixing of its ππ* state with pyrene-guanine charge-transfer states, consistent with the experimentally observed strong electron-phonon coupling. Non-line-narrowed and line-narrowed spectra obtained at 77 and 4.2 K, respectively, are shown to distinguish 4-OHE2-1-N7Gua-dipyrene adducts from 4-OHE2-dipyrene metabolites. These standards have subsequently been used for the spectroscopic identification of depurinating DNA adducts formed in a tissue culture experiment where rat mammary gland tissue was treated with the estrogen quinone E2-3,4-Q. The depurinating adduct formed is 4-OHE2-1- N7Gua.

Original languageEnglish (US)
Pages (from-to)1339-1345
Number of pages7
JournalChemical Research in Toxicology
Volume11
Issue number11
DOIs
StatePublished - 1998
Externally publishedYes

ASJC Scopus subject areas

  • Toxicology

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