Ipso substitution of bisphenol A catalyzed by microsomal cytochrome P450 and enhancement of estrogenic activity

Shigeo Nakamura, Yoshito Tezuka, Atsuko Ushiyama, Chiaki Kawashima, Yumina Kitagawara, Kyoko Takahashi, Shigeru Ohta, Tadahiko Mashino

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Bisphenol A (BPA), an industrial chemical with estrogenic activity, was investigated as a substrate for the ipso-metabolism catalyzed by microsomal cytochrome P450 (P450). BPA was expected to be transformed to a quinol via an ipso-addition reaction; however, hydroquinone (HQ) was detected as a metabolite via an ipso-substitution reaction. Isopropenylphenol (IPP) and hydroxycumyl alcohol (HCA) were also produced as eliminated metabolites by C-C bond scission via ipso-substitution. Incorporation of the 18O atom to HCA from H218O suggested the presence of a carbocation intermediate. Bulkiness of p-substituted group of BPA and/or stability of the eliminated carbocation intermediate may cause ipso-substitution of BPA. CYP3A4 and CYP3A5 showed higher activity for ipso-substitution. CYP2D6*1 also showed the activity; however, the other 9 isozymes did not. IPP showed ER-binding activity in the same degree of BPA. Furthermore, the ER-binding activity of HCA was about a hundred times greater than that of BPA. These results suggested that this new metabolic pathway contributes to the activation of the estrogenic activity of BPA.

Original languageEnglish
Pages (from-to)92-95
Number of pages4
JournalToxicology Letters
Volume203
Issue number1
DOIs
Publication statusPublished - 2011 May 30

Keywords

  • Bisphenol A
  • Cytochrome P450
  • Estrogenic activity
  • Metabolic activation

ASJC Scopus subject areas

  • Toxicology

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