VOL. 2, No. 3, July 2005

H. K. Bhat [2005] Med Hypotheses Res 2: 449-468.

Role of Estrogen Metabolism and Oxidative Stress in
Estrogen-Induced Carcinogenesis

Hari K. Bhat*

Department of Environmental Health Sciences, Mailman School of Public Health, 60 Haven
Avenue-B1, Columbia University, New York 10032, USA

Abstract. Oxidative stress resulting from metabolic breakdown products of estrogens is
suggested to play an important role in estrogen-induced carcinogenic process. Estrogens can
be activated by cytochrome P450 enzymes to hydroxy estrogens (catechol estrogens). The
tumorigenic estrogen metabolites, such as those of 17β-estradiol (βE2) and diethylstilbestrol
(DES), are capable of redox cycling that results in the formation of reactive oxygen species
(ROS) and free radicals, and consequently leads to oxidative stress. It has been shown that
carcinogenic estrogens are capable of producing higher levels of oxidative stress than poorly
carcinogenic or noncarcinogenic estrogens in vivo as well as in vitro. Data also suggest that
the oxidant stress potential of estrogens depends on their ability to form catechol estrogens,
and this ability is correlated with their carcinogenic potential. It is suggested that the
oxidative stress caused by estrogens may act in concert with the estrogen receptor (ER)-
mediated signaling pathways, leading to DNA damage, altered expression of genes critical to
the control of cellular proliferation and defense against oxidative stress, and thus contribute
to the development of estrogen-dependent tumors. Based on the available scientific data, the
US federal government has added estrogens to the list of cancer-causing agents. Thus, studies
aimed at understanding of the mechanisms of estrogen-induced carcinogenesis have
important implications in the understanding and treatment of not just estrogen-, but in
general, hormone-induced neoplasia. This review will attempt to summarize the importance
of oxidative stress in estrogen-induced carcinogenesis.

*Address all correspondence to: Dr. Hari K. Bhat, Department of Environmental Health
Sciences, Mailman School of Public Health, Columbia University, 60 Haven Avenue-B1, New
York, NY 10032, USA. Phone: 212-543-4128. Fax: 212-543-4129. E-Mail:

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