title: Biotransformation of bisphenol AF to its major glucuronide metabolite reduces estrogenic activity.
abstract: Bisphenol AF (BPAF), an endocrine disrupting chemical, can induce estrogenic activity through binding to estrogen receptor (ER). However, the metabolism of BPAF in vivo and the estrogenic activity of its metabolites remain unknown. In the present study, we identified four metabolites including BPAF diglucuronide, BPAF glucuronide (BPAF-G), BPAF glucuronide dehydrated and BPAF sulfate in the urine of Sprague-Dawley (SD) rats. BPAF-G was further characterized by nuclear magnetic resonance (NMR). After treatment with a single dose of BPAF, BPAF was metabolized rapidly to BPAF-G, as detected in the plasma of SD rats. Biotransformation of BPAF to BPAF-G was confirmed with human liver microsomes (HLM), and Vmax of glucuronidation for HLM was 11.6 nmol/min/mg. We also found that BPAF glucuronidation could be mediated through several human recombinant UDP-glucuronosyltransferases (UGTs) including UGT1A1, UGT1A3, UGT1A8, UGT1A9, UGT2B4, UGT2B7, UGT2B15 and UGT2B17, among which UGT2B7 showed the highest efficiency of glucuronidation. To explain the biological function of BPAF biotransformation, the estrogenic activities of BPAF and BPAF-G were evaluated in ER-positive breast cancer T47D and MCF7 cells. BPAF significantly stimulates ER-regulated gene expression and cell proliferation at the dose of 100 nM and 1 μM in breast cancer cells. However, BPAF-G did not show any induction of estrogenic activity at the same dosages, implying that formation of BPAF-G is a potential host defense mechanism against BPAF. Based on our study, biotransformation of BPAF to BPAF-G can eliminate BPAF-induced estrogenic activity, which is therefore considered as reducing the potential threat to human beings.
authors.affiliation: Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Control and Prevention, Beijing, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Control and Prevention, Beijing, China ; School of Public Health and Family Medicine, Capital Medical University, Beijing, China.
authors.forename: Yunjia
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Control and Prevention, Beijing, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Control and Prevention, Beijing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yin
authors.affiliation: Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Control and Prevention, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Control and Prevention, Beijing, China.
authors.forename: Yixing
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Control and Prevention, Beijing, China ; School of Public Health and Family Medicine, Capital Medical University, Beijing, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Shao
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000493:pharmacokinetics* / Q000494:pharmacology; D001711:Biotransformation / Q000187:drug effects; D045744:Cell Line, Tumor; D052244:Endocrine Disruptors / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D020719:Glucuronides / Q000378:metabolism*; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D010636:Phenols / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D005466:Fluorocarbons; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D052244:Endocrine Disruptors; D020719:Glucuronides; D010636:Phenols; C583074:bisphenol AF; D005466:Fluorocarbons; D000098826:Bisphenol A Compounds