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

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 (E(2)) is thought to be oxidized to 4-hydroxyestradiol and then to E(2)-3,4-quinone, which reacts with DNA leading to apurinic sites. These sites represent premutagenic lesions. Additionally, E(2)-3,4-quinone can undergo redox cycling with E(2)-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 mutagenic 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 cII 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 E(2)-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.

• Authors: Zhonglin Zhao, Wieslawa Kosinska, Michael Khmelnitsky, Ercole L Cavalieri, Eleanor G Rogan, Dhrubajyoti Chakravarti, Peter G Sacks, Joseph B Guttenplan
• Journal: Chemical research in toxicology (Chem Res Toxicol) Vol. 19 Issue 3 Pg. 475-9 (Mar 2006) ISSN: 0893-228X [Print] United States
• PMID: 16544955 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Catechols
• Estrogens, Catechol
• Indicators and Reagents
• Mutagens
• Estradiol
• DNA
• 2-hydroxyestradiol
• 4-hydroxyestradiol

Topics

• Animals
• Catechols (chemistry)
• DNA (biosynthesis, genetics)
• Dose-Response Relationship, Drug
• Embryo, Mammalian (cytology)
• Estradiol (analogs & derivatives, toxicity)
• Estrogens, Catechol
• Indicators and Reagents
• Mutagenesis
• Mutagens
• Rats
• Rats, Inbred BB
• Reverse Transcriptase Polymerase Chain Reaction