http://www.dietcan.net/docs/Polifenoles%20en%20alimentos%20y%20biodisponibilidad.pdf

Polyphenols: food sources and bioavailability

[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.

This chapter is an update of the data on substrates, reactions, inducers, and inhibitors of human CYP enzymes published previously by Rendic and DiCarlo (1), now covering selection of the literature through 2001 in the reference section. The data are presented in a tabular form (Table 1) to provide a framework for predicting and interpreting the new P450 metabolic data. The data are formatted in an Excel format as most suitable for off-line searching and management of the Web-database. The data are presented as stated by the author(s) and in the case when several references are cited the data are presented according to the latest published information. The searchable database is available either as an Excel file (for information contact the author), or as a Web-searchable database (Human P450 Metabolism Database, www.gentest.com) enabling the readers easy and quick approach to the latest updates on human CYP metabolic reactions.

Summary of information on human cyp enzymes: human p450 metabolism data

In the past decade there has been considerable progress in the characterization of individual human P450 enzymes. These advances were initiated by early work on the purification of individual enzymes from human liver and other sources. The early work in the area was guided by a focus on the most abundant and easily purified enzymes.1–4It is now apparent, in retrospect, that these proteins were in the 2C and 3A families. Efforts were shifted to attempts to purify individual P450s on the basis of catalytic activities with the evidence that in some cases a single P450 could be identified in this way; e.g., the P450 now known as P450 2D6 was found to be under monogenic control. 5 The approach is technically demanding because of the need to do separations in the presence of detergents and then remove them before analysis of catalytic activity. Nevertheless, human P450s 1A1,6 1A2,7 2A6,8 2C8,9 2C9,9,10 2D67,11,12 2E1 13,14 3A4,15 3A5,16 4A11,17 and lanosterol 14α-demethylase18 were isolated in this general manner. Another approach that has been used, sometimes in a mode complementary to catalytic specificity, is purification on the basis of immunochemical similarity to animal P450s. 7,11,19,20

Human Cytochrome P450 Enzymes

Estrogen is a known risk factor in human breast cancer. In rodent models, estradiol has been shown to induce tumors in those tissues in which this hormone is predominantly converted to the catechol metabolite 4-hydroxyestradiol by a specific 4-hydroxylase enzyme, whereas tumors fail to develop in organs in which 2-hydroxylation predominates. We have now found that microsomes prepared from human mammary adenocarcinoma and fibroadenoma predominantly catalyze the metabolic 4-hydroxylation of estradiol (ratios of 4-hydroxyestradiol/2-hydroxyestradiol formation in adenocarcinoma and fibroadenoma, 3.8 and 3.7, respectively). In contrast, microsomes from normal tissue obtained either from breast cancer patients or from reduction mammoplasty operations expressed comparable estradiol 2- and 4-hydroxylase activities (corresponding ratios, 1.3 and 0.7, respectively). An elevated ratio of 4-/2-hydroxyestradiol formation in neoplastic mammary tissue may therefore provide a useful marker of benign or malignant breast tumors and may indicate a mechanistic role of 4-hydroxyestradiol in tumor development.

https://www.pnas.org/content/pnas/93/8/3294.full.pdf

4-Hydroxylation of estrogens as marker of human mammary tumors

Estradiol is converted to catechol estrogens via 2- and 4-hydroxylation by cytochrome P450 enzymes. 4-Hydroxyestradiol elicits biological activities distinct from estradiol, most notably an oxidant stress response induced by free radicals generated by metabolic redox cycling reactions. In this study, we have examined 2- and 4-hydroxylation of estradiol by microsomes of human uterine myometrium and of associated myomata. In all eight cases studied, estradiol 4-hydroxylation by myoma has been substantially elevated relative to surrounding myometrial tissue (minimum, 2-fold; mean, 5-fold). Estradiol 2-hydroxylation in myomata occurs at much lower rates than 4-hydroxylation (ratio of 4-hydroxyestradiol/2-hydroxyestradiol, 7.9 +/- 1.4) and does not significantly differ from rates in surrounding myometrial tissue. Rates of myometrial 2-hydroxylation of estradiol were also not significantly different from values in patients without myomata. We have used various inhibitors to establish that 4-hydroxylation is catalyzed by a completely different cytochrome P450 than 2-hydroxylation. In myoma, alpha-naphthoflavone and a set of ethynyl polycyclic hydrocarbon inhibitors (5 microM) each inhibited 4-hydroxylation more efficiently (up to 90%) than 2-hydroxylation (up to 40%), indicating > 10-fold differences in Ki ( 5 microM). These activities were clearly distinguished from the selective 2-hydroxylation of estradiol in placenta by aromatase reported previously (low Km, inhibition by Fadrozole hydrochloride or ICI D1033). 4-Hydroxylation was also selectively inhibited relative to 2-hydroxylation by antibodies raised against cytochrome P450 IB1 (rat) (53 vs. 17%). These data indicate that specific 4-hydroxylation of estradiol in human uterine tissues is catalyzed by a form(s) of cytochrome P450 related to P450 IB1, which contribute(s) little to 2-hydroxylation. This enzyme(s) is therefore a marker for uterine myomata and may play a role in the etiology of the tumor.

https://www.pnas.org/content/pnas/92/20/9220.full.pdf

4-Hydroxylation of estradiol by human uterine myometrium and myoma microsomes: implications for the mechanism of uterine tumorigenesis

Metabolic Deglucuronidation and Demethylation of Estrogen Conjugates as a Source of Parent Estrogens and Catecholestrogen Metabolites in Syrian Hamster Kidney, a Target Organ of Estrogen-Induced Tumorigenesis

Cytochrome P450 Metabolism of Estradiol in Hamster Liver and Kidney

BACKGROUND

Long-term treatment of Noble (NBL) rats with testosterone (T) and estradiol-17β (E2) induces dysplasia in the dorsolateral lobe (DLP) but not in the ventral lobe (VP) of the rat prostate. The aim of this study was to determine whether metabolic conversion of E2 to catechol estrogens (CEs), which are potentially genotoxic, is a mechanism of estrogen carcinogenicity in this tissue.



METHODS

Male NBL rats were treated simultaneously with T and E2, or left untreated, for 16 weeks after which time the liver, VP, and DLP were excised for microsomal preparations. 3H-E2 metabolites generated in microsomal incubates were separated by high-performance liquid chromatography (HPLC) and identified by coelution with known E2 metabolites.



RESULTS

2- and 4-hydroxyestrogens were detected at high levels in hepatic microsomal incubates, and at extremely low levels in prostatic microsomal incubates. T + E2 treatment of rats did not increase the formation of these prostatic and hepatic metabolites.



CONCLUSIONS

These results do not support CE formation as a mediating step in estrogen-induced tumorigenesis in the rat prostate. Prostate 30:256–262, 1997. © 1997 Wiley-Liss, Inc.

Mary Jo Ricci

Papers

4-Hydroxylation of estrogens as marker of human mammary tumors

4-Hydroxylation of estradiol by human uterine myometrium and myoma microsomes: implications for the mechanism of uterine tumorigenesis

Metabolic Deglucuronidation and Demethylation of Estrogen Conjugates as a Source of Parent Estrogens and Catecholestrogen Metabolites in Syrian Hamster Kidney, a Target Organ of Estrogen-Induced Tumorigenesis

Cytochrome P450 Metabolism of Estradiol in Hamster Liver and Kidney

Effect of combined testosterone and estradiol‐17β treatment on the metabolism of E2 in the prostate and liver of noble rats