title: Influence of metabolism on endocrine activities of bisphenol S.
abstract: Bisphenol S (BPS; bis[4-hydroxyphenyl]sulfone) is commonly used as a replacement for bisphenol A in numerous consumer products. The main goal of this study was to examine the influence of different metabolic reactions that BPS undergoes on the endocrine activity. We demonstrate that hydroxylation of the aromatic ring of BPS, catalyzed mainly by the cytochrome P450 enzymes CYP3A4 and CYP2C9, is its major in-vitro phase I biotransformation. Nevertheless, coupled oxidative-conjugative reactions analyses revealed that glucuronidation and formation of BPS glucuronide is the predominant BPS metabolic pathway. BPS reactive metabolites that can be tracked as glutathione conjugates were not detected in the present study. Two in-vitro systems were used to evaluate the endocrine activity of BPS and its two main metabolites, BPS glucuronide and hydroxylated BPS 4-(4-hydroxy-benzenesulfonyl)-benzene-1,2-diol (BPSM1). In addition, we have tested two structural analogs of BPS, bis[4-(2-hydroxyetoxy)phenyl]sulfone (BHEPS) and 4,4-sulfonylbis(2-methylphenol) (dBPS). The test systems were yeast cells, for evaluating estrogenic and androgenic activities, and the GH3.TRE-Luc reporter cell line for measuring thyroid hormone activity. BPS and BPSM1 were weak agonists of the estrogen receptor, EC50 values of 8.4 × 10(-5) M and 6.7 × 10(-4) M, respectively. Additionally, BPSM1 exhibited weak antagonistic activity toward the thyroid hormone receptor, with an IC50 of 4.3 × 10(-5) M. In contrast to BPSM1, BPS glucuronide was inactive in these assays, inhibiting neither the estrogen nor the thyroid hormone receptors. Hence, glucuronidation appears to be the most important pathway for both BPS metabolism and detoxification.
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Darja Gramec
authors.initials: DG
authors.lastname: Skledar
authors.affiliation: Faculty of Medicine, University of Maribor, Maribor, Slovenia.
authors.forename: Jan
authors.initials: J
authors.lastname: Schmidt
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Anja
authors.initials: A
authors.lastname: Fic
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Ivana
authors.initials: I
authors.lastname: Klopčič
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Jurij
authors.initials: J
authors.lastname: Trontelj
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Marija Sollner
authors.initials: MS
authors.lastname: Dolenc
authors.affiliation: Division of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
authors.forename: Moshe
authors.initials: M
authors.lastname: Finel
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia. Electronic address: lucija.peterlin@ffa.uni-lj.si.
authors.forename: Lucija Peterlin
authors.initials: LP
authors.lastname: Mašič
mesh_terms: D000818:Animals; D001711:Biotransformation; D002460:Cell Line; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D052244:Endocrine Disruptors / Q000378:metabolism* / Q000633:toxicity; D020719:Glucuronides / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D008658:Inactivation, Metabolic; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010636:Phenols / Q000378:metabolism* / Q000633:toxicity; D011960:Receptors, Estrogen / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000037:antagonists & inhibitors*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D013450:Sulfones / Q000378:metabolism* / Q000633:toxicity; D000098831:Bisphenol S Compounds
chemical_list: D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; D052244:Endocrine Disruptors; D020719:Glucuronides; D010636:Phenols; D011960:Receptors, Estrogen; D011988:Receptors, Thyroid Hormone; D013450:Sulfones; C543008:bisphenol S; D000098831:Bisphenol S Compounds; C450260:CYP2C9 protein, human; C510163:CYP3A4 protein, human
keywords: Bisphenol S; Estrogenic effects; Glucuronidation; Oxidative metabolism; Thyroid hormone receptor