Guillemette Chantal, Bélanger Alain, Lépine Johanie
Canada Research Chair in Pharmacogenomics and laboratory of Pharmacogenomics, CHUL Research Center, Québec, Canada.
Breast Cancer Res. 2004;6(6):246-54. doi: 10.1186/bcr936. Epub 2004 Sep 27.
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.
乳腺组织是雌二醇（E2）主要代谢转化的场所，该转化由特定的细胞色素P450羟基化作用以及儿茶酚-O-甲基转移酶的甲基化作用介导。除了E2本身，最近的研究结果突出了4-羟基化雌激素代谢产物作为化学介质的重要性及其与乳腺癌发生和进展的联系，而相反，2-甲氧基化雌激素似乎具有保护作用。最近的数据还表明，乳腺组织拥有通过尿苷二磷酸葡萄糖醛酸基转移酶（UGTs）催化的结合作用使E2及其氧化和甲氧基化代谢产物失活并消除的酶机制，这涉及葡糖醛酸的共价添加。与雌激素的其他代谢途径相反，UGT介导的过程导致形成无生物活性的葡糖醛酸苷，并易于从组织排泄到循环中。本综述阐述了关于负责E2及其代谢产物葡糖醛酸化的UGT酶鉴定的最新研究结果，以及关于它们在乳腺癌中潜在作用的证据。
