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.
