Elsevier

Methods in Enzymology

Volume 378, 2004, Pages 110-123
Methods in Enzymology

Quinoids Formed from Estrogens and Antiestrogens

https://doi.org/10.1016/S0076-6879(04)78006-4Get rights and content

Publisher Summary

This chapter focuses on the role of quinoids in the DNA damage induced by estrogens and antiestrogen metabolites. Selective estrogen receptor modulators (SERMs) are developed for the treatment of menopause-associated osteoporosis, with a primary application being in the treatment and prevention of breast cancer in postmenopausal women. The most widely used SERM is tamoxifen, which is extensively used for the treatment of hormone-dependent breast cancer and more recently as a chemopreventive agent in women at risk for breast cancer; however, like the estrogens associated with estrogen replacement therapy, tamoxifen can also lead to an increased endometrial cancer risk. The molecular mechanism(s) involved in the carcinogenic action of estrogens and antiestrogens still remains both controversial and elusive. Both can be metabolized to reactive intermediates such as o-quinones and quinone methides, which could cause DNA damage directly through the formation of DNA adducts or indirectly through the generation of reactive oxygen species that oxidize DNA. It is shown that quinones and quinone methides can be formed from both estrogens and antiestrogens. These reactive species can cause damage in cells either through alkylation of cellular macromolecules and/or through generation of reactive oxygen species.

Introduction

A firm link between female reproductive variables and increased risk of cancer developing in the breast and endometrium has been established from epidemiological studies.1, 2, 3, 4 The longer women are exposed to estrogens, either through early menarche and late menopause and⧸or through estrogen replacement therapy, the higher is the risk of certain hormone-dependent cancer developing. It used to be thought that the numerous benefits of estrogen replacement therapy, including the relief of menopausal symptoms, decrease in coronary heart disease, osteoporosis, stroke, and Alzheimer's disease, justified the use of long-term estrogen replacement therapy. However, the release of the Women's Health Initiative Study in July 2002 cast serious doubt on this paradigm for the treatment of postmenopausal women.5 This study was halted 3 years early because of significant increases in breast cancer, coronary heart disease, stroke, and cardiovascular disease, with the most recent data suggesting an increase in vascular dementia in women older than 65 taking estrogen replacement therapy.6 These troubling findings have emphasized the crucial need for developing alternative estrogen replacement formulations that maintain the beneficial properties of estrogens without generating adverse side effects. To develop such “wonder” drugs, it is first necessary to understand the cytotoxic mechanisms of estrogens and in particular their ability to cause DNA damage.

Selective estrogen receptor modulators (SERMs) have been developed for treatment of menopause-associated osteoporosis, with a primary application being in the treatment and prevention of breast cancer in postmenopausal women.7 The most widely used SERM is tamoxifen (Fig. 1), which has been extensively used for the treatment of hormone-dependent breast cancer and more recently as a chemopreventive agent in women at risk for breast cancer; however, like the estrogens associated with estrogen replacement therapy, tamoxifen also can lead to an increased endometrial cancer risk.8, 9 The molecular mechanism(s) involved in the carcinogenic action of estrogens and antiestrogens still remains both controversial and elusive.10 They can both be metabolized to reactive intermediates such as o-quinones and quinone methides (Fig. 2), which could cause DNA damage directly through the formation of DNA adducts or indirectly through the generation of reactive oxygen species that oxidize DNA.11 The focus of this report is the role of quinoids in the DNA damage induced by estrogens and antiestrogen metabolites.

Section snippets

Experimental Procedures

Caution: Estrogen and antiestrogen metabolites were handled in accordance with the NIH Guidelines for the Laboratory Use of Chemical Carcinogens.12 All solvents and chemicals were purchased from either Aldrich Chemical Company (Milwaukee, WI) or Fisher Scientific (Itasca, IL) unless stated otherwise. 4-Hydroxytamoxifen,13 4-hydroxytoremifene,13 3,4-dihydroxytamoxifen,14 and 3,4-dihydroxytoremifene15 were synthesized as described previously. Droloxifene16 and raloxifene17 were synthesized

Results and Discussion

Tamoxifen, and its active metabolite, 4-hydroxytamoxifen, are antiestrogens that can be viewed as the prototypical SERMs. However, the search to optimize the mix of estrogenic and antiestrogenic activity continues to generate new SERMs, many of which may be categorized into families, which one might expect to show similar chemical and biological reactivity. As we collect data on the chemical and biological pathways leading to formation of reactive intermediates and the reactions of these

Concluding Remarks

In conclusion, it has been shown that quinones and quinone methides can be formed from both estrogens and antiestrogens. These reactive species can cause damage in cells either through alkylation of cellular macromolecules and⧸or through generation of reactive oxygen species. The type of DNA adducts formed vary considerably with the structure and reactivity of the quinoid with some generating unstable adducts, which would readily depurinate, and others forming stable lesions, which would have

Acknowledgements

This work was supported by NIH Grants CA73638 and CA79870.

References (54)

  • J.G Liehr

    Mutat. Res.

    (1990)
  • J.L Bolton

    Toxicology

    (2002)
  • J.L Bolton et al.

    Chem.-Biol. Interact.

    (1995)
  • J Embrechts et al.

    J. Am. Soc. Mass Spectrom.

    (2003)
  • Y Yoshie et al.

    Free Radic. Biol. Med.

    (1998)
  • R.H Purdy et al.

    FEBS Lett.

    (1982)
  • B.E Henderson et al.

    Cancer Res.

    (1988)
  • H.S Feigelson et al.

    Carcinogenesis

    (1996)
  • G.A Colditz

    J. Natl. Cancer Inst.

    (1998)
  • J.E Rossouw et al.

    JAMA

    (2002)
  • S.A Shumaker et al.

    JAMA

    (2003)
  • T.A Grese et al.

    Current Pharm. Design.

    (1998)
  • M.A Seoud et al.

    Obstet. Gynecol.

    (1993)
  • D.H Phillips

    Carcinogenesis

    (2001)
  • R.F Service

    Science

    (1998)
  • J.L Bolton et al.

    Chem. Res. Toxicol.

    (1998)
  • (1981)
  • S Gauthier et al.

    J. Org. Chem.

    (1996)
  • F Zhang et al.

    Chem. Res. Toxicol.

    (2000)
  • D Yao et al.

    Chem. Res. Toxicol.

    (2001)
  • R McCage et al.

    J. Med. Chem.

    (1989)
  • C.D Jones et al.

    J. Med. Chem.

    (1984)
  • L Shen et al.

    Carcinogenesis

    (1997)
  • M Chang et al.

    Chem. Res. Toxicol.

    (1998)
  • S.L Iverson et al.

    Chem. Res. Toxicol.

    (1996)
  • M.M Marques et al.

    Carcinogenesis

    (1997)
  • J.A Thompson et al.

    Drug Metab. Dispos.

    (1987)
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