[Axelrod et al. (1958)][1] first described the enzyme-catalyzed O- methylation of catecholamines and other catechols in the late 1950s. The enzyme responsible for the O- methylation, catechol- O -methyltransferase (COMT; EC[2.1.1.6][2]),2 was partly purified and characterized by the same group ([

Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors.

Cytochrome P450 enzymes that metabolize estrogens are expressed in the mammary gland, uterus, brain and other target tissues for estrogen action, and this results in the formation of hydroxylated estrogens in these tissues. Estradiol metabolites formed in target tissues at or near estrogen receptors may either be inactive or have important biological effects, and changes in the activities of estrogen-metabolizing enzymes in target tissues may profoundly influence estrogen action. Although some active estrogen metabolites exert hormonal effects in target tissues by interaction with the classical estrogen receptor, other metabolites appear to elicit unique biological responses that are not associated with activation of this receptor. Therefore, some of the many actions of estradiol may not be caused by estradiol 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. This is an important area in need of more research. The present paper represents a review of the literature and perspectives by the authors on the functional role of estrogen metabolism in target tissues.

https://www.hormonebalance.org/images/documents/Zhu%2098estrogen%20metabolism%20in%20target%20cells%20Carc.pdf

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

Cancer is a disease that begins with mutation of critical genes: oncogenes and tumor suppressor genes. Our research on carcinogenic aromatic hydrocarbons indicates that depurinating hydrocarbon–DNA adducts generate oncogenic mutations found in mouse skin papillomas (Proc. Natl. Acad. Sci. USA 92:10422, 1995). These mutations arise by mis-replication of unrepaired apurinic sites derived from the loss of depurinating adducts. This relationship led us to postulate that oxidation of the carcinogenic 4-hydroxy catechol estrogens (CE) of estrone (E1) and estradiol (E2) to catechol estrogen-3,4-quinones (CE-3, 4-Q) results in electrophilic intermediates that covalently bind to DNA to form depurinating adducts. The resultant apurinic sites in critical genes can generate mutations that may initiate various human cancers. The noncarcinogenic 2-hydroxy CE are oxidized to CE-2,3-Q and form only stable DNA adducts. As reported here, the CE-3,4-Q were bound to DNA in vitro to form the depurinating adduct 4-OHE1(E2)-1(α,β)-N7Gua at 59–213 μmol/mol DNA–phosphate whereas the level of stable adducts was 0.1 μmol/mol DNA–phosphate. In female Sprague–Dawley rats treated by intramammillary injection of E2-3,4-Q (200 nmol) at four mammary glands, the mammary tissue contained 2.3 μmol 4-OHE2-1(α,β)-N7Gua/molDNA–phosphate. When 4-OHE1(E2) were activated by horseradish peroxidase, lactoperoxidase, or cytochrome P450, 87–440 μmol of 4-OHE1(E2)-1(α, β)-N7Gua was formed. After treatment with 4-OHE2, rat mammary tissue contained 1.4 μmol of adduct/mol DNA–phosphate. In each case, the level of stable adducts was negligible. These results, complemented by other data, strongly support the hypothesis that CE-3,4-Q are endogenous tumor initiators.

https://www.pnas.org/content/pnas/94/20/10937.full.pdf

Molecular origin of cancer: Catechol estrogen-3,4-quinones as endogenous tumor initiators

Estrogens induce tumors in laboratory animals and have been associated with breast and uterine cancers in humans. In relation to the role of estrogens in the induction of cancer, we examine formation of DNA adducts by reactive electrophilic estrogen metabolites, formation of reactive oxygen species by estrogens and the resulting indirect DNA damage by these oxidants, and, finally, genomic and gene mutations induced by estrogens. Quinone intermediates derived by oxidation of the catechol estrogens 4-hydroxyestradiol or 4-hydroxyestrone may react with purine bases of DNA to form depurinating adducts that generate highly mutagenic apurinic sites. In contrast, quinones of 2-hydroxylated estrogens produce less harmful, stable DNA adducts. The catechol estrogen metabolites may also generate potentially mutagenic oxygen radicals by metabolic redox cycling or other mechanisms. Several types of indirect DNA damage are caused by estrogen-induced oxidants, such as oxidized DNA bases, DNA strand breakage, and adduct formation by reactive aldehydes derived from lipid hydroperoxides. Estradiol and the synthetic estrogen diethylstilbestrol also induce numerical and structural chromosomal aberrations and several types of gene mutations in cells in culture and in vivo. In conclusion, estrogens, including the natural hormones estradiol and estrone, must be considered genotoxic carcinogens on the basis of the evidence outlined in this chapter.

/pdf/estrogens-as-endogenous-genotoxic-agents-dna-adducts-and-1bfxpl2yvw.pdf

Estrogens as endogenous genotoxic agents--DNA adducts and mutations.

The role of estrogen in the initiation of breast cancer

Evidence for a role of estrogen metabolism in hormonal carcinogenesis was obtained with the Syrian hamster as an in vivo model system. Both natural and synthetic estrogens are capable of inducing a high incidence of renal carcinomas in this species. A high incidence of hepatocellular carcinomas can also be induced in the hamster with synthetic estrogens such as ethinyl estradiol or diethylstilbestrol, provided alpha-naphthoflavone (ANF) is present in the diet. Although steroid receptor-mediated hormonal events appear to be intimately involved in the process of in vivo cell transformation of both tissues, certain observations strongly suggest that nonhormonal events are also important. Despite their potent estrogenic activity at the doses used, ethinyl estradiol and alpha-zearalanol induce relatively low renal tumor incidences after 9.0 and 10.0 months of continuous treatment, respectively. A role for the metabolism of estrogens to reactive intermediates is also suggested by studies showing estrogen-induced renal tumorigenesis can be partially inhibited by concomitant administration of ANF or ascorbic acid. Consistent with this is the general correlation between the amount of catechol estrogen formed by a compound, as mediated by estrogen 2-/4-hydroxylase, and renal carcinogenicity data. Recently, additional supporting evidence has been obtained from studies involving the irreversible binding of reactive metabolites of steroidal or stilbene estrogens to hamster liver microsomal proteins.

Li Sa

Papers

Estrogen carcinogenesis in Syrian hamster tissues: role of metabolism.