Bioactivation of dibrominated biphenyls by cytochrome P450 activity to metabolites with estrogenic activity and estrogen sulfotransferase inhibition capacity

M.M.H. van Lipzig, J.N.M. Commandeur, F.J.J. de Kanter, M.C. Damsten, N.P.E. Vermeulen, E. Maat, E. de Groot, A.M. Brouwer, M.H.A. Kester, T.D. Visser, J.H.N. Meerman

    Research output: Contribution to JournalArticleAcademicpeer-review

    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 EC
    Original languageEnglish
    Pages (from-to)1691-1700
    Number of pages10
    JournalChemical Research in Toxicology
    Volume18
    Issue number11
    Early online date12 Oct 2005
    DOIs
    Publication statusPublished - 1 Nov 2005

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