TY - JOUR
T1 - Glucuronidation of hydroxylated polybrominated diphenyl ethers and their modulation of estrogen UDP-glucuronosyltransferases
AU - Lai, Yongquan
AU - Lu, Minghua
AU - LIN, Shuhai
AU - CAI, Zongwei
N1 - Funding Information:
The authors thank the special post-graduate studentship program of “Persistent Toxic Substances” from Research Grant Council, University Grants Committee of Hong Kong SAR. Financial support of Collaborative Research Fund from the Research Grant Council (HKBU1/CRF08) and the collaborative fund from National Sciences Foundation of China (NSFC20621703) is acknowledged. We also thank Dr. Michael H.W. Lam (Department of Biology and Chemistry, City University of Hong Kong) for providing the OH-PBDEs and 6-CH 3 O-BDE-47.
PY - 2012/2
Y1 - 2012/2
N2 - 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 t1/2 value of 3.86min, while 6-OH-BDE-137 having four bromine atoms at phenolic ring was the poorest substrate with t1/2 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 IC50 values varying from 3.80 to 129.38μM, while 3'-OH-BDE-100 exhibited stimulating effects on 3-glucuronidation with EC50 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 Ki 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.
AB - 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 t1/2 value of 3.86min, while 6-OH-BDE-137 having four bromine atoms at phenolic ring was the poorest substrate with t1/2 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 IC50 values varying from 3.80 to 129.38μM, while 3'-OH-BDE-100 exhibited stimulating effects on 3-glucuronidation with EC50 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 Ki 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.
KW - 17β-Estradiol
KW - Glucuronidation modulation
KW - Hydroxylated polybrominated diphenyl ethers
KW - Structure-activity relationship
UR - http://www.scopus.com/inward/record.url?scp=84856052508&partnerID=8YFLogxK
U2 - 10.1016/j.chemosphere.2011.10.047
DO - 10.1016/j.chemosphere.2011.10.047
M3 - Journal article
C2 - 22119418
AN - SCOPUS:84856052508
SN - 0045-6535
VL - 86
SP - 727
EP - 734
JO - Chemosphere
JF - Chemosphere
IS - 7
ER -