Mutagenic activity of 4-hydroxyestradiol, but not 2-hydroxyestradiol, in BB rat2 embryonic cells, and the mutational spectrum of 4-hydroxyestradiol

Zhonglin Zhao, Wieslawa Kosinska, Michael Khmelnitsky, Ercole Cavalieri, Eleanor G Rogan, Dhrubajyoti Chakravarti, Peter G. Sacks, Joseph B. Guttenplan

Research output: Contribution to journalArticle

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Abstract

Estrogens are hypothesized to contribute to breast cancer via estrogen receptor-mediated increases in cell proliferation and via genotoxic processes leading to mutations. In this latter process, estradiol (E2) is thought to be oxidized to 4-hydroxyestradiol and then to E2-3,4- quinone, which reacts with DNA leading to apurinic sites. These sites represent premutagenic lesions. Additionally, E2-3,4-quinone can undergo redox cycling with E2-3,4-hydroquinone, leading to the release of reactive oxygen species. Although there is evidence that estradiol and E 2-3,4-quinone are carcinogenic or mutugenic in several systems, 4-hydroxyestradiol, a key intermediate in the proposed genotoxic pathway, has thus far been negative in mutagenesis assays. Another major metabolite of estradiol, 2-hydroxyestradiol, is essentially inactive in carcinogenicity or mutagenicity assays. Here, we report that when using multiple low-dose exposures 4-hydroxyestradiol is mutagenic in the cll assay in BB rat2 cells. Under similar conditions, 2-hydroxyestradiol is inactive. Furthermore, the mutational spectrum of 4-hydroxyestradiol contains a considerable proportion of mutations at A:T base pairs, consistent with the known ability of E2-3,4- quinone to form a significant fraction of DNA adducts at adenines. Thus, the results of this study support the proposal that estradiol can contribute to carcinogenesis via a genotoxic pathway.

Original languageEnglish (US)
Pages (from-to)475-479
Number of pages5
JournalChemical Research in Toxicology
Volume19
Issue number3
DOIs
StatePublished - Mar 1 2006

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Estradiol
Assays
Mutagenesis
Mutation
DNA Adducts
Cell proliferation
Adenine
Metabolites
Base Pairing
Estrogen Receptors
Oxidation-Reduction
Reactive Oxygen Species
Estrogens
Carcinogenesis
Cell Proliferation
Breast Neoplasms
4-hydroxyestradiol
benzoquinone
2-hydroxyestradiol
DNA

ASJC Scopus subject areas

  • Toxicology

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Mutagenic activity of 4-hydroxyestradiol, but not 2-hydroxyestradiol, in BB rat2 embryonic cells, and the mutational spectrum of 4-hydroxyestradiol. / Zhao, Zhonglin; Kosinska, Wieslawa; Khmelnitsky, Michael; Cavalieri, Ercole; Rogan, Eleanor G; Chakravarti, Dhrubajyoti; Sacks, Peter G.; Guttenplan, Joseph B.

In: Chemical Research in Toxicology, Vol. 19, No. 3, 01.03.2006, p. 475-479.

Research output: Contribution to journalArticle

Zhao, Zhonglin ; Kosinska, Wieslawa ; Khmelnitsky, Michael ; Cavalieri, Ercole ; Rogan, Eleanor G ; Chakravarti, Dhrubajyoti ; Sacks, Peter G. ; Guttenplan, Joseph B. / Mutagenic activity of 4-hydroxyestradiol, but not 2-hydroxyestradiol, in BB rat2 embryonic cells, and the mutational spectrum of 4-hydroxyestradiol. In: Chemical Research in Toxicology. 2006 ; Vol. 19, No. 3. pp. 475-479.
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