METABOLISM OF CATECHOL ESTROGENS

Project: Research project

Project Details

Description

Hormones can play an important role in both the initiation and promotion
of cancer. Hormonal carcinogenesis is often characterized by both tissue
and species specificity. In many instances, the basis for this
specificity is unclear. In addition, the potential role that metabolism
plays in hormonal carcinogenesis remains unclear. In this respect, the
catechol estrogens have been suggested to be the putative reactive
metabolites responsible for some of the carcinogenic effects of
estradiol, and the majority of the literature addressing the role of
metabolism in hormonal carcinogenicity is derived from studies on these
metabolites. Remarkably however, knowledge of the disposition of the
catechol estrogens is poorly understood. This proposal therefore
addresses these deficiencies and focuses on the in vivo and in vitro
metabolism of the catechol estrogens. In particular, we plan to
determine the relative importance of catechol estrogen oxidation and
thioether formation, and catechol estrogen methylation, to the overall
metabolism of catechol estrogens. Several lines of evidence suggest that
the quantitative (and perhaps mechanistic) significance of catechol
estrogen oxidation and thioether formation may have been underestimated.
Indeed, there is a growing body of evidence demonstrating the biological
(re)activity of a variety of quinone-thioethers. For example, we have
recently shown that the conjugation of certain quinones with glutathione
(GSH) leads to the formation of potent and selective nephrotoxicants.
Moreover, the National Toxicology Program recently determined that
hydroquinone (HQ) was nephrocarcinogenic in rats. We have also described
the in vivo formation of several GSH conjugates of HQ, which are
nephrotoxic when administered to rats (the role of toxicity [and
mitogenesis] in carcinogenicity remains a contentious issue !). In the
Golden Syrian hamster, metabolism of estrogens to catechols, and their
corresponding ortho-quinones, may be an important step in the
nephrocarcinogenic process. The basis of this species specificity is not
known. However, while the liver appears proficient at metabolizing
estrogens to catecholic metabolites, the kidney exhibits relatively low
activity and plasma levels of both estrogens and their catecholic
metabolites are low. Although the catechol estrogens are known to
interact with thiols, in particular GSH, to form thioether conjugates,
the quantitative importance of this pathway remains unclear. We
hypothesize that quinone-thioethers derived from the catechol estrogens
may play an important mechanistic role in estradiol mediated
carcinogenicity. A comprehensive understanding of both the in vivo and
in vitro disposition of the catechol estrogens will not only permit a
critical evaluation of this hypothesis, but will also provide information
essential to assess the role of metabolism in estradiol mediated
carcinogenicity and its role in the species specificity.
StatusFinished
Effective start/end date8/1/927/31/97

Funding

  • National Institutes of Health
  • National Institutes of Health: $106,694.00
  • National Institutes of Health
  • National Institutes of Health: $108,198.00

ASJC

  • Medicine(all)

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