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Metabolic Inactivation of Estrogens in Breast Tissue By View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by PubMed Central Breast Cancer Research Vol 6 No 6 Guillemette et al. Review Metabolic inactivation of estrogens in breast tissue by UDP- glucuronosyltransferase enzymes: an overview Chantal Guillemette1–3, Alain Bélanger2,4 and Johanie Lépine1–3 1Canada Research Chair in Pharmacogenomics and laboratory of Pharmacogenomics, CHUL Research Center, Québec, Canada 2Oncology and Molecular Endocrinology Research Center, CHUL Research Center, Québec, Canada 3Faculty of Pharmacy, Laval University, Québec, Canada 4Faculty of Medicine, Laval University, Québec, Canada Corresponding author: Chantal Guillemette, [email protected] Published: 27 September 2004 Breast Cancer Res 2004, 6:246-254 (DOI 10.1186/bcr936) © 2004 BioMed Central Ltd Abstract The breast tissue is the site of major metabolic conversions of estradiol (E2) mediated by specific cytochromes P450 hydroxylations and methylation by catechol-O-methyltransferase. In addition to E2 itself, recent findings highlight the significance of 4-hydroxylated estrogen metabolites as chemical mediators and their link to breast cancer development and progression, whereas, in opposition, 2- methoxylated estrogens appear to be protective. Recent data also indicate that breast tissue possesses enzymatic machinery to inactivate and eliminate E2 and its oxidized and methoxylated metabolites through conjugation catalyzed by UDP-glucuronosyltransferases (UGTs), which involves the covalent addition of glucuronic acid. In opposition to other metabolic pathways of estrogen, the UGT-mediated process leads to the formation of glucuronides that are devoid of biologic activity and are readily excreted from the tissue into the circulation. 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. Keywords: breast carcinoma, catecholestrogen, estrogen metabolism, genetic polymorphism, UDP-glucuronosyltransferase Introduction estrogen exposure for lengthy periods of time may induce Estrogens are essential for development of the repro- breast cancer [1–3]. ductive system in women, in whom they exert beneficial effects in a large number of tissues, including breast, Several observations have also associated in situ bone, brain, and cardiovascular system. In contrast, the production of hydroxylated estrogen metabolites, namely proliferation and genetic instability induced by estrogens catecholestrogens, with the development of estrogen- in breast and uterus have been considered to increase sensitive cancers. Oxidative reactions are also important further the likelihood that normal cells will transform into a because 2- and 4-hydroxylated metabolites possess malignant type. Over the past 30 years a large number of distinctive biologic properties as compared with estradiol case–control and cohort studies have been conducted (E2), the 4-hydroxylated metabolites being particularly that examined circulating levels of estrogens and/or their important to the carcinogenic effects of estrogen [4–6]. It urinary excretion to detect any differences in estrogen is also important to emphasize that these metabolic concentrations that may contribute to cancer. Based on reactions not only take place in the liver but also in their findings it has been suggested that increased estrogen target tissues such as breast, ovary and uterus, CI = confidence interval; COMT = catechol-O-methyltransferase; CYP = cytochrome P450; E1 = estrone; E1S = estrone sulfate; E2 = estradiol; ER 246 = estrogen receptor; OHCE = hydroxy-catecholestrogen; OR = odds ratio; UGT = UDP-glucuronosyltransferase. Available online http://breast-cancer-research.com/content/6/6/246 Figure 1 Estrogen biosynthesis and metabolism in breast tissue. In breast tissue, estrogens come directly from ovaries or they are synthesized from androgens secreted by the adrenals. (1) The first metabolic pathway of estrogen involves the transformation of estradiol (E2) to estrone (E1) by β β 17 -hydroxysteroid dehydrogenase (17 -HSD) and its subsequent conjugation to estrone sulfate (E1S) by estrogen sulfotransferase. (2) Both E2 and E1 can be oxidized by the action of different cytochrome P450 enzymes to generate 2- and 4-hydroxy-catecholestrogen (OHCE). (3) These metabolites can be further methoxylated by catechol-O-methyltransferase (COMT). (4) UDP-glucuronosyltransferases (UGTs) are able to conjugate parent estrogens E2 and E1, as well as their derivatives 2/4-OHCE and 2/4-methoxy-catecholestrogen (MeOCE). The resulting estrogen glucuronides are devoid of biologic activities. AR, androgen receptor; 3β-HSD, 3β-hydroxysteroid dehydrogenase; CYP19, aromatase; ∆5-diol, androstenediol; DHT, dihydrotestosterone; ER, estrogen receptor; MeO, methoxy; OH, hydroxy; testo, testosterone. and thus they play a critical role in the local homeostasis sex steroid hormones in women vary tremendously of E2 and its metabolites. throughout life. During ovarian cycles the follicles and the corpus luteum are important sources of E2 and estrone In addition to the hydroxylation of estrogen, it has been (E1), the serum concentrations of which range from 50 to known for many years that estrogen can be conjugated in 300 pg/ml and from 30 to 250 pg/ml, respectively breast tissue. Conjugative estrogen metabolism includes [20–23]. E1 sulfate (E1S) is also found in the circulation sulfonation [7,8], glucuronidation [9,10] and O- (concentration approximately 1 ng/ml), but it is probably methylation [11], which are catalyzed by sulfotransferases, formed by estrogen sulfotransferase, which is present in UDP-glucuronosyltransferases (UGTs) and catechol-O- several tissues (Fig. 1). In adult women the term methyltransferase (COMT), respectively. Sulfates and ‘circulating estrogen’ is generally used to refer to E2, E1, glucuronides are the most abundant circulating estrogen and E1S; the latter two represent a form of estrogen conjugates [12]. Several recent observations support a storage and are precursors of E2 [20,22]. In addition to role for UGT enzymes in relation to estrogen metabolism the direct secretion of estrogens by the ovaries into the and cancer risk in estrogen target tissues [13–19]. This bloodstream, a second source of estrogen in adult women review addresses the most recent findings regarding the is through adrenal steroids such as dehydro- identification of UGT enzymes responsible for the epiandrosterone, its sulfate, and androstenedione (referred glucuronidation of E2 and its metabolites, and their as C19 steroids); these are converted to estrogen by the potential role in breast cancer susceptibility. aromatase enzyme (CYP19), which is expressed in several extra-ovarian tissues, particularly adipose tissue [22,24,25]. Site of production and secretion of estrogens in women during aging At menopause, however, production of estrogen by the In comparison with men, who exhibit relatively constant ovaries is abolished. Despite the marked decline in blood levels of androgen after puberty, circulating levels of adrenal C19 steroid production observed in humans after 247 Breast Cancer Research Vol 6 No 6 Guillemette et al. age 30 years, these steroid precursors become the only human CYPs to estrogen was thoroughly characterized by source of estrogen as substrates of CYP19 (Fig. 1) Lee and coworkers [36], and they concluded that the [25–27]. Thus, the profile in the circulation is markedly major oxidative products formed from E2 by CYPs are the modified in postmenopausal women as compared with 2-hydroxy-catecholestrogens (OHCEs) and 4-OHCEs premenopausal women; serum concentrations of E2 are (Fig. 1). As indicated above, these catecholestrogens relatively low (about 2–10 pg/ml), whereas E1 (about possess distinct biologic properties as compared with E2. 10–30 pg/ml) and E1S (about 150 pg/ml) exceed E2 For instance, several groups have postulated that the concentrations [28]. By contrast, the concentrations of E2 depurinating adducts formed from 4-OHCEs may in estrogen sensitive tissues are not significantly generate mutations that initiate cancer, whereas 2-OHCE decreased, despite the low serum E2 levels in menopausal metabolites may protect against cancer [4,6,35,37–40]. women [29,30]. In addition, several observations indicate that, in the absence of ovarian production of estrogen, the The formation of 2-OHCEs and 4-OHCEs in breast tissue low concentrations of E2 in the circulation are not was recently studied by Rogan and coworkers [41]. Those representative of E2 content in tissue [23,29–33]. Indeed, investigators quantified the total pool of conjugated and only a small fraction of E2 would be released from the nonconjugated E1, E2, their hydroxylated metabolites at various tissues because of further local conversion of E2 positions 2 and 4, and methylated derivatives of into E1 and E1S, in addition to a series of polar metabolites catecholestrogens in breast tissue samples, after treat- (Fig. 1). Thus, despite marked changes in blood estrogen ment of tissue homogenates with glucuronidase/sulfatase levels, the tissue content of estrogens and polar to release the corresponding unconjugated steroids. In metabolites appears to remain relatively constant during tissues obtained from healthy women, they found that aging. That a significant proportion of breast cancers levels of the 2- and 4-hydroxy and/or methoxy metabolites occur in postmenopausal
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