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Chemical research in toxicology2010; 23(8); 1365-1373; doi: 10.1021/tx1001282

Redox cycling of catechol estrogens generating apurinic/apyrimidinic sites and 8-oxo-deoxyguanosine via reactive oxygen species differentiates equine and human estrogens.

Abstract: Metabolic activation of estrogens to catechols and further oxidation to highly reactive o-quinones generates DNA damage including apurinic/apyrimidinic (AP) sites. 4-Hydroxyequilenin (4-OHEN) is the major catechol metabolite of equine estrogens present in estrogen replacement formulations, known to cause DNA strand breaks, oxidized bases, and stable and depurinating adducts. However, the direct formation of AP sites by 4-OHEN has not been characterized. In the present study, the induction of AP sites in vitro by 4-OHEN and the endogenous catechol estrogen metabolite, 4-hydroxyestrone (4-OHE), was examined by an aldehyde reactive probe assay. Both 4-OHEN and 4-OHE can significantly enhance the levels of AP sites in calf thymus DNA in the presence of the redox cycling agents, copper ion and NADPH. The B-ring unsaturated catechol 4-OHEN induced AP sites without added copper, whereas 4-OHE required copper. AP sites were also generated much more rapidly by 4-OHEN. For both catechol estrogens, the levels of AP sites correlated linearly with 8-oxo-dG levels, implying that depuriniation resulted from reactive oxygen species (ROS) rather than depurination of estrogen-DNA adducts. ROS modulators such as catalase, which scavenges hydrogen peroxide and a Cu(I) chelator, blocked the formation of AP sites. In MCF-7 breast cancer cells, 4-OHEN significantly enhanced the formation of AP sites with added NADH. In contrast, no significant induction of AP sites was detected in 4-OHE-treated cells. The greater redox activity of the equine catechol estrogen produces rapid oxidative DNA damage via ROS, which is enhanced by redox cycling agents and interestingly by NADPH-dependent quinone oxidoreductase.
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Publication Date: 2010-06-01 PubMed ID: 20509668PubMed Central: PMC2922465DOI: 10.1021/tx1001282Google Scholar: Lookup
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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.

This study explores how the metabolic activation of estrogens into catechols and their further oxidation into o-quinones, such as 4-hydroxyequilenin (4-OHEN), can lead to DNA damage. The researchers discovered that both 4-OHEN and another common catechol estrogen metabolite, 4-hydroxyestrone (4-OHE), can increase levels of DNA damage in vitro when coupled with redox cycling agents. Notably, the research indicates that this DNA damage results from reactive oxygen species (ROS) rather than depurination of estrogen-DNA adducts.

Metabolic Activation of Estrogens

  • The researchers investigated the metabolic activation of estrogens to catechols and their further oxidation to highly reactive o-quinones. These processes cause DNA damage, centering around apurinic/apyrimidinic (AP) sites.
  • The primary catechol metabolite of equine estrogens, 4-hydroxyequilenin (4-OHEN), known to cause DNA strand breaks, oxidized bases, and stable and depurinating adducts was the focal point of this research.

Induction of DNA Damage in Vitro

  • This study examined the in vitro generation of AP sites by 4-OHEN and 4-hydroxyestrone (4-OHE), another endogenous catechol estrogen metabolite, with the use of the aldehyde reactive probe assay.
  • An interesting observation was that both 4-OHEN and 4-OHE can significantly enhance the levels of AP sites in calf thymus DNA in the presence of the redox cycling agents, a copper ion, and NADPH.
  • Here, the 4-OHEN induced AP sites without the need for additional copper, unlike 4-OHE. Moreover, AP sites were generated more rapidly by 4-OHEN.

Role of Reactive Oxygen Species

  • The research found that for both tested catechol estrogens, the levels of AP sites correlated linearly with 8-oxo-dG levels, indicating that the depurination resulted from reactive oxygen species (ROS) rather than depurination of estrogen-DNA adducts.
  • The influence of ROS was further underpinned by the fact that the formation of AP sites was blocked by ROS modulators such as catalase, which scavenges hydrogen peroxide, and a Cu(I) chelator.
  • In MCF-7 breast cancer cells, 4-OHEN considerably increased the formation of AP sites alongside added NADH. Comparatively, the treatment of cells with 4-OHE yielded no significant induction of AP sites.

The Significance of the Findings

  • The implication of this research is the enlightening discovery of the redox cycling behavior of catechol estrogens, differentiating equine and human estrogens.
  • Overall, the greater redox activity of the equine catechol estrogen results in rapid oxidative DNA damage via ROS, further potentiated by redox cycling agents and intriguingly by NADPH-dependent quinone oxidoreductase.

Cite This Article

APA
Wang Z, Chandrasena ER, Yuan Y, Peng KW, van Breemen RB, Thatcher GR, Bolton JL. (2010). Redox cycling of catechol estrogens generating apurinic/apyrimidinic sites and 8-oxo-deoxyguanosine via reactive oxygen species differentiates equine and human estrogens. Chem Res Toxicol, 23(8), 1365-1373. https://doi.org/10.1021/tx1001282

Publication

Chemical research in toxicology
ISSN: 1520-5010
NlmUniqueID: 8807448
Country: United States
Language: English
Volume: 23
Issue: 8
Pages: 1365-1373

Researcher Affiliations

Wang, Zhican
  • Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612-7231, USA.
Chandrasena, Esala R
    Yuan, Yang
      Peng, Kuan-wei
        van Breemen, Richard B
          Thatcher, Gregory R J
            Bolton, Judy L

              MeSH Terms

              • 8-Hydroxy-2'-Deoxyguanosine
              • Animals
              • Cattle
              • Cell Line, Tumor
              • Chelating Agents / pharmacology
              • Copper / chemistry
              • Copper / metabolism
              • DNA / metabolism
              • DNA Damage
              • DNA, Neoplasm / metabolism
              • Deoxyguanosine / analogs & derivatives
              • Deoxyguanosine / metabolism
              • Equilenin / analogs & derivatives
              • Equilenin / chemistry
              • Equilenin / metabolism
              • Estrogens, Catechol / chemistry
              • Estrogens, Catechol / metabolism
              • Estrogens, Catechol / pharmacology
              • Free Radical Scavengers / pharmacology
              • Horses
              • Humans
              • Hydrogen Peroxide / pharmacology
              • Hydroxyestrones / chemistry
              • Hydroxyestrones / metabolism
              • Molecular Structure
              • NADP / chemistry
              • NADP / metabolism
              • Oxidation-Reduction / drug effects
              • Reactive Oxygen Species / metabolism
              • Structure-Activity Relationship

              Grant Funding

              • R01 CA130037 / NCI NIH HHS
              • R01 CA130037-05 / NCI NIH HHS
              • CA130037 / NCI NIH HHS

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