title: Bioactivation of dibrominated biphenyls by cytochrome P450 activity to metabolites with estrogenic activity and estrogen sulfotransferase inhibition capacity.
abstract: Exposure of humans and wildlife to xenobiotics, such as halogenated biphenyls, that interfere with the endogenous estrogen balance may lead to endocrine disruption. Such compounds may either mimic or block estradiol's action by agonistic or antagonistic action, respectively. They may also affect endogenous estradiol concentrations by induction or inhibition of enzymes that metabolize estradiol. In the present study, we demonstrate that estrogenic metabolites of two brominated biphenyls, 2,2'-dibromobiphenyl (2,2'-DBB) and 4,4'-dibromobiphenyl (4,4'-DBB), are formed by rat liver microsomal cytochrome P450 (CYP) activity. Bioactivation of 2,2'-DBB and 4,4'-DBB yielded various mono- and dihydroxylated bromobiphenyl metabolites, which were collected by preparative HPLC and analyzed by LC/MS. Several of the metabolites bound to the estrogen receptor (ER) activated the ER and inhibited human estrogen sulfotransferase (hEST). Seven monohydroxylated metabolites were positively identified using synthetic monohydroxylated reference compounds. These synthetic monohydroxylated bromobiphenyls also bound to and activated the ER and inhibited hEST. The highest ER affinity was observed for 4-OH-2,2'-DBB, with an EC50 of 6.6 nM. The highest ER activation was observed for 4-OH-3,4'-DBB (EC50 of 74 nM) while 4-OH-4'-MBB and 4-OH-2,2'-DBB induced a supramaximal (as compared to estradiol) ER activation. The strongest hEST inhibition was found with 4-OH-3,4'-DBB (EC50 = 40 nM). In conclusion, we show that two dibrominated biphenyls are bioactivated by CYP activity into very potent estrogenic metabolites and inhibitors of hEST. These findings are of vital importance for accurate risk assessment of exposure to environmental contaminants, such as halogenated biphenyls. Neglecting bioactivation through biotransformation will lead to underestimation of health risks of this class of xenobiotics.
authors.affiliation: Leiden/Amsterdam Center for Drug Research, Department of Pharmacochemistry, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands.
authors.forename: Marola M H
authors.initials: MM
authors.lastname: van Lipzig
authors.forename: Jan N
authors.initials: JN
authors.lastname: Commandeur
authors.forename: Frans J J
authors.initials: FJ
authors.lastname: de Kanter
authors.forename: Micaela C
authors.initials: MC
authors.lastname: Damsten
authors.forename: Nico P E
authors.initials: NP
authors.lastname: Vermeulen
authors.forename: Evelina
authors.initials: E
authors.lastname: Maat
authors.forename: Ed J
authors.initials: EJ
authors.lastname: Groot
authors.forename: Abraham
authors.initials: A
authors.lastname: Brouwer
authors.forename: Monique H A
authors.initials: MH
authors.lastname: Kester
authors.forename: Theo J
authors.initials: TJ
authors.lastname: Visser
authors.forename: John H N
authors.initials: JH
authors.lastname: Meerman
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011960:Receptors, Estrogen / Q000378:metabolism; D012756:Sheep; D015238:Sulfotransferases / Q000037:antagonists & inhibitors*; D014599:Uterus / Q000378:metabolism
chemical_list: D001713:Biphenyl Compounds; D004967:Estrogens; D011960:Receptors, Estrogen; D003577:Cytochrome P-450 Enzyme System; C065774:4,4'-dibromobiphenyl; D015238:Sulfotransferases; C020122:estrone sulfotransferase