Journal Article

Catechol estrogen conjugates and DNA adducts in the kidney of male Syrian golden hamsters treated with 4-hydroxyestradiol: potential biomarkers for estrogen-initiated cancer

Prabu Devanesan, Rosa Todorovic, Jiang Zhao, Michael L. Gross, Eleanor G. Rogan and Ercole L. Cavalieri

in Carcinogenesis

Volume 22, issue 3, pages 489-497
Published in print March 2001 | ISSN: 0143-3334
Published online March 2001 | e-ISSN: 1460-2180 | DOI: https://dx.doi.org/10.1093/carcin/22.3.489
Catechol estrogen conjugates and DNA adducts in the kidney of male Syrian golden hamsters treated with 4-hydroxyestradiol: potential biomarkers for estrogen-initiated cancer

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Formation of depurinating adducts by reaction of catechol estrogen-3,4-quinones with DNA was proposed to be a tumor initiating event by estrogens [E.L.Cavalieri et al. (1997) Proc. Natl Acad. Sci. USA, 94, 10937–10942]. Under estrogenic imbalance, oxidation of catechol estrogens to quinones may compete with their detoxification by protective enzymes. The quinones formed can be detoxified by reaction with glutathione (GSH) or can covalently bind to DNA. To provide more support for this hypothesis, we developed a method to identify and quantify GSH, cysteine (Cys) and N-acetylCys conjugates of 4-hydroxyestrogens (4-OHE) in the kidneys of male Syrian hamsters treated with 4-hydroxyestradiol (4-OHE2) by intraperitoneal injection. The highest level of conjugates was observed 1 h after treatment, and almost none was detected after 24 h. Dose–response studies indicated conjugate formation after treatment with 0.5 μmol of 4-OHE2/100 g body weight, and formation increased up to a treatment level of 12 μmol/100 g body weight. GSH, Cys and N-acetylCys conjugates of 4-OHE were identified in the picomole range by high-performance liquid chromatography (HPLC) with multichannel electrochemical detection and confirmed by HPLC/tandem mass spectrometry. Treatment of tissue homogenates with β-glucuronidase/sulfatase at 37°C for 6 h before extraction resulted in a 12- to 20-fold increase in Cys conjugates from picomole to nanomole levels. Similar enhancement was observed by just incubating the tissue at 37°C for 6 h. Evidence for the 4-OHE-1-N7Gua depurinating adducts was obtained by mass spectrometry. We conclude that GSH and Cys conjugates of the 4-OHE and the 4-OHE-N7Gua adducts can be utilized as biomarkers to detect estrogenic imbalance and potential susceptibility to tumor initiation.

Keywords: CE, catechol estrogen(s); CE-Q, catechol estrogen-3,4-quinone(s); Cys, cysteine; E1, estrone; E2, 17β-estradiol; ESI, electrospray ionization; GSH, glutathione; HPLC, high-performance liquid chromatography; LC/MS, liquid chromatography/mass spectrometry; NAcCys, N-acetylcysteine; OHE, hydroxyestrogen(s); -SG, glutathione moiety.

Journal Article.  4837 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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