Tissue-specific synthesis and oxidative metabolism of estrogens.

  title={Tissue-specific synthesis and oxidative metabolism of estrogens.},
  author={Colin R Jefcoate and Joachim G. Liehr and R. J. Santen and Thomas R. Sutter and James D. Yager and Wei Yue and Steven J. Santner and Rajeshwar R Tekmal and Laurence M. Demers and Robert J. Pauley and Frederick Naftolin and Gil Mor and Lev M. Berstein},
  journal={Journal of the National Cancer Institute. Monographs},
Estrogen exposure represents the major known risk factor for development of breast cancer in women and is implicated in the development of prostate cancer in men. Human breast tissue has been shown to be a site of oxidative metabolism of estrogen due to the presence of specific cytochrome P450 enzymes. The oxidative metabolism of 17beta-estradiol (E2) to E2-3,4-quinone metabolites by an E2-4-hydroxylase in breast tissue provides a rational hypothesis to explain the mammary carcinogenic effects… 

Estrogen Metabolism: Does the Formation of Estrogen Quinone Provide a Potential Pathway to Breast Carcinogenesis?

The efficiency of the O-methylation pathway is reflected in the extremely short half-life of catechol estrogens, which are the major urinary estrogen metabolites.

Metabolic inactivation of estrogens in breast tissue by UDP-glucuronosyltransferase enzymes: an overview

This review addresses the most recent findings on the identification of UGT enzymes that are responsible for the glucuronidation of E2 and its metabolites, and evidence regarding their potential role in breast cancer.

Potential mechanisms of estrogen quinone carcinogenesis.

The data suggest that other key protein targets for estrogen o-quinones could be redox-sensitive enzymes (i.e, GST P1-1, QR).

Genotoxic metabolites of estradiol in breast: potential mechanism of estradiol induced carcinogenesis

Dissecting the prevention of estrogen-dependent breast carcinogenesis through Nrf2-dependent and independent mechanisms

The use of specific phytochemicals and dietary supplements can inhibit the risk of breast cancer not only by the modulation of several estrogen-activating enzymes but also through the induction of various cytoprotective enzymes that reestablish the homeostatic balance of estrogen metabolism via nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent and independent mechanisms.

The effects of catechol-O-methyltransferase inhibition on estrogen metabolite and oxidative DNA damage levels in estradiol-treated MCF-7 cells.

This study is the first to show that O-methylation of 2- OH E2 by COMT is protective against oxidative DNA damage caused by 2-OH E2, a major oxidative metabolite of E2.

Unbalanced metabolism of endogenous estrogens in the etiology and prevention of human cancer

  • E. CavalieriE. Rogan
  • Biology, Chemistry
    The Journal of Steroid Biochemistry and Molecular Biology
  • 2011



4-Hydroxylation of estrogens as marker of human mammary tumors.

  • J. LiehrM. Ricci
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 1996
It is found that microsomes prepared from human mammary adenocarcinoma and fibroadenoma predominantly catalyze the metabolic 4-hydroxylation of estradiol, which may indicate a mechanistic role of 4-Hydroxyestradiol in tumor development.

Functional role of estrogen metabolism in target cells: review and perspectives.

Some of the many actions of estradiol may not be caused by est radiol per se, but may result from the formation of active estrogen metabolite(s) which function as local mediators or may activate their own unique receptors or effectors.

Increased catechol estrogen metabolism as a risk factor for nonfamilial breast cancer

Metaanalysis supported the conclusion that increased rates of oxidation of estradiol 17‐β to 2‐OH catechols supply the principal proximal human mammary carcinogens active after menarche, and ECE rose linearly exponentially with increasing cancer risk.

Cytochrome P450 metabolism of estradiol in hamster liver and kidney.

The data suggest that estrogen 2-hydroxylation in the hamster kidney is catalyzed by members of the CYP1A and CYP3A families, which also contribute to 4-hydoxylation, and that the majority of 4-Hydroxyestradiol formation in theHamster kidney may be catalyzing by a form(s) of the newly discovered CYP 1B family that has yet to be characterized.

Molecular Mechanisms of Estrogen Carcinogenesis

The examples demonstrate that the parent compounds and their metabolites cause both nongenotoxic cell proliferative effects as well as direct and indirect genotoxic effects, which illustrates the complex nature of estrogen carcinogenesis.

Estrogen carcinogenesis in Syrian hamster tissues: role of metabolism.

Evidence for a role of estrogen metabolism in hormonal carcinogenesis was obtained with the Syrian hamster as an in vivo model system and the general correlation between the amount of catechol estrogen formed by a compound, as mediated by estrogen 2-/4-hydroxylase, and renal carcinogenicity data is consistent.

Catecholestrogen synthesis and metabolism by human breast tumors in vitro.

The enzymes responsible for the synthesis and metabolism of catecholestrogens are present in some breast tumor specimens, suggesting that in such tissues these metabolites may be formed in vivo.

Dual role of oestrogens as hormones and pro-carcinogens: tumour initiation by metabolic activation of oestrogens.

  • J. Liehr
  • Biology, Medicine
    European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation
  • 1997
A mechanism for mammary carcinogenesis is examined, which emphasizes tumour initiation by metabolic activation of oestrogens in combination with cell transformation and growth stimulation by oestrogen receptor-mediated processes.

The carcinogenic activity of ethinyl estrogens is determined by both their hormonal characteristics and their conversion to catechol metabolites.

The hypothesis that estrogen-induced carcinogenesis is mediated by catechol estrogen metabolites is supported and the carcinogenic estrogen MOX is converted to catechl metabolites at lower rates than estradiol, but their methylation may be sterically hindered by the 11 beta-methoxy substituent.