Department of Chemistry
Glucuronidation of hydroxylated polybrominated diphenyl ethers and their modulation of estrogen UDP-glucuronosyltransferases
Polybrominated diphenyl ethers (PBDEs) can be metabolically converted to their hydroxylated metabolites (OH-PBDEs). The estrogenic effects of PBDEs may be mediated by OH-PBDEs, but the mechanisms of which are still not understood. This study investigated the glucuronidation of 11 OH-PBDEs and their potential in modulating UDP-glucuronosyltransferases (UGTs) activity of 17β-estradiol (E2) in rat liver microsomes. The number of bromine atoms at phenolic ring was observed as the most influential factor of OH-PBDEs glucuronidation. 2'-OH-BDE-28 having one bromine atom at phenolic ring showed the fastest metabolic rates with t 1/2 value of 3.86min, while 6-OH-BDE-137 having four bromine atoms at phenolic ring was the poorest substrate with t 1/2 value over 60min. Regarding to the modulation of E2-UGTs activity, the phenolic hydroxyl group in OH-PBDEs played an essential role. Depending on the substitution patterns of bromine and hydroxyl group, OH-PBDEs inhibited or stimulated E2-UGTs activity. Ten of OH-PBDEs inhibited both 3-glucuronidation and 17-glucuronidation of E2 with IC 50 values varying from 3.80 to 129.38μM, while 3'-OH-BDE-100 exhibited stimulating effects on 3-glucuronidation with EC 50 value of 35.95μM. Kinetic analysis suggested noncompetitive inhibition mode of E2 glucuronidation by 3'-OH-BDE-7, 6-OH-BDE-47 and 2'-OH-BDE-68 with K i values varying from 11.95 to 67.22μM. This study demonstrated OH-PBDEs exhibited large interindividual differences in glucuronidation and modulation of E2-UGTs activity. By inhibiting the formation of E2 glucuronidation, OH-PBDEs may increase E2 bioavailability in target tissue, thereby exerting an indirect estrogenic effect. © 2011 Elsevier Ltd.
17β-Estradiol, Glucuronidation modulation, Hydroxylated polybrominated diphenyl ethers, Structure-activity relationship
Source Publication Title
Lai, Yongquan, Minghua Lu, Shuhai Lin, and Zongwei Cai. "Glucuronidation of hydroxylated polybrominated diphenyl ethers and their modulation of estrogen UDP-glucuronosyltransferases." Chemosphere 86.7 (2012): 727-734.