Bisphenol-A glucuronidation in human liver and breast: identification of UDP-glucuronosyltransferases (UGTs) and influence of genetic polymorphisms.
Bisphenol-A glucuronidation in human liver and breast: identification of UDP-glucuronosyltransferases (UGTs) and influence of genetic polymorphisms.
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DOI：
10.3109/00498254.2016.1156784
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发表时间：
2017-01
期刊：
影响因子：
--
通讯作者：
Court MH
中科院分区：
文献类型：
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作者：
Street CM;Zhu Z;Finel M;Court MH
双酚-A 是一种普遍存在的环境污染物，主要通过葡萄糖醛酸化代谢，并与包括乳腺癌在内的多种人类疾病相关。在这里，我们鉴定了 UDP-葡萄糖醛酸基转移酶 (UGT) 和遗传多态性，这些多态性导致人类肝脏和乳房中双酚 A 葡萄糖醛酸化的个体差异。显示出最高双酚 A 葡萄糖醛酸化活性的肝脏 UGT 包括 UGT2B15 和 UGT1A9。相对活性因子归一化表明，UGT2B15 在双酚 A 浓度低于 5 µM 时贡献 > 80% 的活性，而 UGT1A9 在较高浓度下贡献高达 50% 的活性。肝微粒体（46 个供体）的双酚 A 葡萄糖醛酸化范围为 0.25 至 4.3 纳摩尔/分钟/毫克蛋白质。与 *1/*1 和 *1/*22 肝脏相比，在 UGT1A9 *22/*22 肝脏中观察到葡萄糖醛酸化程度高两倍 (P = 0.018)。然而，没有观察到 UGT2B15*2 或 UGT1A1*28 基因型之间的关联。乳腺微粒体（15 名供体）的双酚 A 葡萄糖醛酸化范围为 <0.2 至 56 fmoles/min/mg 蛋白质。能够使双酚 A 葡萄糖醛酸化的 UGT 的乳腺 mRNA 表达以 UGT1A1 最高，其次是 UGT2B4、UGT1A9、UGT1A10、UGT2B7 和 UGT2B15。与不带 UGT1A1*28 等位基因的乳腺组织相比，双酚 A 葡萄糖醛酸化水平低 10 倍以上 (P = 0.006)。 UGT2B15 和 UGT1A9 导致肝脏中葡萄糖醛酸化变异，而 UGT1A1 在乳房中很重要。
Bisphenol-A is a ubiquitous environmental contaminant that is primarily metabolized by glucuronidation and associated with various human diseases including breast cancer. Here we identified UDP-glucuronosyltransferases (UGTs) and genetic polymorphisms responsible for interindividual variability in bisphenol-A glucuronidation in human liver and breast. Hepatic UGTs showing the highest bisphenol-A glucuronidation activity included UGT2B15 and UGT1A9. Relative activity factor normalization indicated that UGT2B15 contributes >80% of activity at bisphenol-A concentrations under 5 µM, while UGT1A9 contributes up to 50% of activity at higher concentrations. Bisphenol-A glucuronidation by liver microsomes (46 donors) ranged from 0.25 to 4.3 nmoles/min/mg protein. Two-fold higher glucuronidation (P = 0.018) was observed in UGT1A9 *22/*22 livers compared with *1/*1 and *1/*22 livers. However, no associations were observed for UGT2B15*2 or UGT1A1*28 genotypes. Bisphenol-A glucuronidation by breast microsomes (15 donors) ranged from <0.2 to 56 fmoles/min/mg protein. Breast mRNA expression of UGTs capable of glucuronidating bisphenol-A was highest for UGT1A1, followed by UGT2B4, UGT1A9, UGT1A10, UGT2B7 and UGT2B15. Bisphenol-A glucuronidation was over 10-fold lower in breast tissues with the UGT1A1*28 allele compared with tissues without this allele (P = 0.006). UGT2B15 and UGT1A9 contribute to glucuronidation variability in liver, while UGT1A1 is important in breast.