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Home / Equine Research Bank / Chem Res Toxicol / Oxidative DNA damage induced by equine estrogen metabolites:...
Chemical research in toxicology2002; 15(4); 512-519; doi: 10.1021/tx0101649

Oxidative DNA damage induced by equine estrogen metabolites: role of estrogen receptor alpha.

Abstract: Excessive exposure to synthetic and endogenous estrogens has been associated with the development of cancer in several tissues. 4-Hydroxyequilenin (4-OHEN), a major metabolite of equine estrogens present in estrogen replacement formulations, has been shown to induce cytotoxic/carcinogenic effects. In the present study, we have found that 4-OHEN caused DNA damage in breast cancer cells, and cells that contain estrogen receptor alpha (S30) are more sensitive to 4-OHEN-mediated DNA damage as compared to estrogen receptor negative cells (MDA-MB-231). For example, concentration-dependent increases in 8-oxo-deoxyguanosine (8-oxo-dG), as measured by LC-MS-MS or by the Fpg comet assay, were only detected in the S30 cells, and the amount of this lesion could be enhanced by agents, which catalyze redox cycling (NADH) or deplete GSH (diethyl maleate). The role of the estrogen receptor in modulating DNA damage was further established in incubations with the ER antagonist tamoxifen, where decreases in 8-oxo-deoxyguanosine were observed. Another equine estrogen metabolite, 4,17 beta-hydroxyequilenin (4,17 beta-OHEN), was found to have the same cytotoxicity and a similar ability to induce reactive oxygen species (ROS), and caused the same oxidative DNA damage in S30 cells as compared to 4-OHEN. However, 4,17 beta-OHEN induced twice as much single strand DNA breaks in S30 cells compared to 4-OHEN. Also 4,17 beta-OHEN was more estrogenic than 4-OHEN as demonstrated by a higher binding affinity for ER alpha and an enhanced induction in activity of estrogen-dependent alkaline phosphatase in Ishikawa cells. These data suggest that the mechanism of DNA damage induced by equine estrogen metabolites could involve oxidative stress and that the estrogen receptor may play a role in this process.
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Publication Date: 2002-04-16 PubMed ID: 11952337DOI: 10.1021/tx0101649Google Scholar: Lookup
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  • Journal Article
  • Research Support
  • U.S. Gov't
  • P.H.S.

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research investigates the impact of metabolites of equine estrogens, specifically 4-Hydroxyequilenin (4-OHEN) and 4,17 beta-hydroxyequilenin (4,17 beta-OHEN), on DNA damage in breast cancer cells. The study finds that exposure to these metabolites can cause oxidative DNA damage, and that this effect is further amplified in cells containing estrogen receptor alpha, potentially suggesting a link between estrogen metabolites, oxidative stress, and DNA damage in the process of cancer development.

Context and Aim of the Research

  • The researchers aim to understand the impact of equine estrogen metabolites, predominantly 4-Hydroxyequilenin (4-OHEN) and 4,17 beta-hydroxyequilenin (4,17 beta-OHEN), on DNA damage within breast cancer cells.
  • This investigation is rooted in the correlation observed between excessive exposure to synthetic and natural estrogens and the development of various cancers.
  • Understanding the mechanisms of DNA damage induced by these metabolites could reveal new insights into cancer development and possible treatment options.

Key Findings

  • 4-OHEN, a primary metabolite in estrogen replacement formulations, caused DNA damage in breast cancer cells, specifically in cells that contain estrogen receptor alpha (S30).
  • Such cells were found to be more prone to 4-OHEN-induced DNA damage in comparison to estrogen receptor negative cells (MDA-MB-231).
  • Increasing 4-OHEN concentrations amplified the occurrence of an oxidative DNA lesion called 8-oxo-deoxyguanosine (8-oxo-dG) in S30 cells. The amount of this DNA lesion could be intensified by substances that catalyze redox cycling (like NADH) or deplete GSH (such as diethyl maleate).
  • The facilitative role of the estrogen receptor in DNA damage was confirmed when observed decreases in 8-oxo-deoxyguanosine levels were coincided with the use of an ER antagonist, tamoxifen.
  • Another metabolite, 4,17 beta-OHEN, was discovered to possess similar cytotoxicity to 4-OHEN and was likewise able to generate reactive oxygen species (ROS), which also led to similar levels of DNA damage in S30 cells.
  • However, 4,17 beta-OHEN was found to induce nearly double the single strand DNA breaks in comparison to 4-OHEN, suggesting it might have more damaging potential.
  • 4,17 beta-OHEN was identified as more estrogenic than 4-OHEN, indicated by a higher binding affinity for ER alpha and increased induction of estrogen-dependent alkaline phosphatase activity in Ishikawa cells.

Conclusion and Implications

  • The investigation concludes by suggesting that DNA damage caused by equine estrogen metabolites could be due to oxidative stress and that the estrogen receptor might have a significant role in this process.
  • The results are critical in understanding the implications of excessive estrogen exposure, particularly in terms of its association with the development of certain forms of cancer.
  • Furthermore, treatments like tamoxifen that target the estrogen receptor might play an essential role in limiting DNA damage and might be effective in the context of treatments for cancers related to estrogen exposure.

Cite This Article

APA
Liu X, Yao J, Pisha E, Yang Y, Hua Y, van Breemen RB, Bolton JL. (2002). Oxidative DNA damage induced by equine estrogen metabolites: role of estrogen receptor alpha. Chem Res Toxicol, 15(4), 512-519. https://doi.org/10.1021/tx0101649

Publication

Chemical research in toxicology
ISSN: 0893-228X
NlmUniqueID: 8807448
Country: United States
Language: English
Volume: 15
Issue: 4
Pages: 512-519

Researcher Affiliations

Liu, Xuemei
  • Department of Medicinal Chemistry and Pharmacognosy (M/C 781), College of Pharmacy, The University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, USA.
Yao, Jiaqin
    Pisha, Emily
      Yang, Yanan
        Hua, Yousheng
          van Breemen, Richard B
            Bolton, Judy L

              MeSH Terms

              • Binding, Competitive
              • Breast Neoplasms / genetics
              • Breast Neoplasms / metabolism
              • Breast Neoplasms / pathology
              • Cell Survival / drug effects
              • Comet Assay
              • DNA Damage / drug effects
              • DNA, Neoplasm / analysis
              • Dose-Response Relationship, Drug
              • Equilenin / analogs & derivatives
              • Equilenin / toxicity
              • Estradiol Congeners / toxicity
              • Estrogen Receptor alpha
              • Female
              • Humans
              • Reactive Oxygen Species / metabolism
              • Receptors, Estrogen / antagonists & inhibitors
              • Receptors, Estrogen / metabolism
              • Selective Estrogen Receptor Modulators / pharmacology
              • Tamoxifen / pharmacology
              • Tumor Cells, Cultured / drug effects
              • Tumor Cells, Cultured / metabolism

              Grant Funding

              • CA70771 / NCI NIH HHS
              • CA73638 / NCI NIH HHS

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