Bioactivation of Dibrominated Biphenyls by Cytochrome P450 Activity to Metabolites with Estrogenic Activity and Estrogen Sulfotransferase Inhibition Capacity

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• 作者：Marola M. H. van Lipzig ; Jan N. Commandeur ; Frans J. J. de Kanter ; Micaela C. Damsten ; Nico P. E. Vermeulen ; Evelina Maat ; Ed J. Groot ; Abraham Brouwer ; Monique H. A. Kester ; Theo J. Visser ; and John
• 刊名：Chemical Research in Toxicology
• 出版年：2005
• 出版时间：November 2005
• 年：2005
• 卷：18
• 期：11
• 页码：1691 - 1700
• 全文大小：163K
• 年卷期：v.18,no.11(November 2005)
• ISSN：1520-5010

文摘

Exposure of humans and wildlife to xenobiotics, such as halogenated biphenyls, that interferewith the endogenous estrogen balance may lead to endocrine disruption. Such compounds mayeither mimic or block estradiol's action by agonistic or antagonistic action, respectively. Theymay also affect endogenous estradiol concentrations by induction or inhibition of enzymes thatmetabolize estradiol. In the present study, we demonstrate that estrogenic metabolites of twobrominated 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'-DBBand 4,4'-DBB yielded various mono- and dihydroxylated bromobiphenyl metabolites, whichwere collected by preparative HPLC and analyzed by LC/MS. Several of the metabolites boundto the estrogen receptor (ER) activated the ER and inhibited human estrogen sulfotransferase(hEST). Seven monohydroxylated metabolites were positively identified using syntheticmonohydroxylated reference compounds. These synthetic monohydroxylated bromobiphenylsalso bound to and activated the ER and inhibited hEST. The highest ER affinity was observedfor 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 arebioactivated 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 environmentalcontaminants, such as halogenated biphenyls. Neglecting bioactivation through biotransformation will lead to underestimation of health risks of this class of xenobiotics.