Metabolic inactivation of estrogens in breast tissue by UDP-glucuronosyltransferase enzymes: an overview

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-methytransferase. 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.

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 17β-hydroxysteroid dehydrogenase (17βHSD) and its subsequent conjugation to estrone sulfate (E₁S) by estrogen sulfotransferase. (2) Both E₂ and E₁ can be oxidized by the action of different cytochromes P450 (CYPs) 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 there 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; Δ5-diol, androstenediol; DHT, dihydrotestosterone; ER, estrogen receptor; MeO, methoxy; OH, hydroxy; testo, testosterone.

Figure 2

Regioselectivity of human UDP-glucuronosyltransferases (UGTs) for parent estrogens estrone (E₁) and estradiol (E₂), their catechol estrogens metabolites 2-hydroxy (OH)E₁/E₂ and 4-OHE₁/E₂, and their methoxy metabolites 2-methoxy (MeO)E₁/E₂ and 4-MeOE₁/E₂. Red is used for E₂ and its metabolites, whereas blue refers to E₁ and its metabolites.