title: Glucuronidation of hydroxylated polybrominated diphenyl ethers and their modulation of estrogen UDP-glucuronosyltransferases.
abstract: 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 3.86 min, while 6-OH-BDE-137 having four bromine atoms at phenolic ring was the poorest substrate with t(1/2) value over 60 min. 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 129.38 μM, while 3'-OH-BDE-100 exhibited stimulating effects on 3-glucuronidation with EC(50) value of 35.95 μM. 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 67.22 μM. 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.
authors: Department of Chemistry, Hong Kong Baptist University, Hong Kong SAR, China.
authors: Yongquan
authors: Y
authors: Lai
authors: Minghua
authors: M
authors: Lu
authors: Shuhai
authors: S
authors: Lin
authors: Zongwei
authors: Z
authors: Cai
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D052244:Endocrine Disruptors / Q000737:chemistry* / Q000494:pharmacology*; D004967:Estrogens / Q000378:metabolism*; D020723:Glucuronic Acid / Q000737:chemistry*; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055768:Halogenated Diphenyl Ethers / Q000737:chemistry* / Q000494:pharmacology*; D054879:Halogenation; D006900:Hydroxylation; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D052244:Endocrine Disruptors; D004967:Estrogens; D055768:Halogenated Diphenyl Ethers; D020723:Glucuronic Acid; D014453:Glucuronosyltransferase