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, Ercole Cavalieri

Research output: Contribution to journalArticle

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Abstract

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 complete 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.

Original languageEnglish (US)
Pages (from-to)489-497
Number of pages9
JournalCarcinogenesis
Volume22
Issue number3
StatePublished - Mar 21 2001

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Catechol Estrogens
DNA Adducts
Mesocricetus
Cysteine
Estrogens
Biomarkers
Kidney
Quinones
Neoplasms
High Pressure Liquid Chromatography
Body Weight
Sulfatases
Glucuronidase
DNA
Therapeutics
Tandem Mass Spectrometry
Intraperitoneal Injections
Glutathione
Mass Spectrometry
4-hydroxyestradiol

ASJC Scopus subject areas

  • Cancer Research

Cite this

Catechol estrogen conjugates and DNA adducts in the kidney of male Syrian golden hamsters treated with 4-hydroxyestradiol : Potential biomarkers for estrogen-initiated cancer. / Devanesan, Prabu; Todorovic, Rosa; Zhao, Jiang; Gross, Michael L.; Rogan, Eleanor G; Cavalieri, Ercole.

In: Carcinogenesis, Vol. 22, No. 3, 21.03.2001, p. 489-497.

Research output: Contribution to journalArticle

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