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

37 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 H2 18O 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

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Cytochrome P-450 Enzyme System
Substitution reactions
Cytochrome P-450 CYP3A
Alcohols
Metabolites
Hydroquinones
Industrial chemicals
Cytochrome P-450 CYP2D6
Addition reactions
Metabolic Networks and Pathways
bisphenol A
Metabolism
Isoenzymes
Chemical activation
Atoms
Substrates

Keywords

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

ASJC Scopus subject areas

  • Toxicology

Cite this

Ipso substitution of bisphenol A catalyzed by microsomal cytochrome P450 and enhancement of estrogenic activity. / Nakamura, Shigeo; Tezuka, Yoshito; Ushiyama, Atsuko; Kawashima, Chiaki; Kitagawara, Yumina; Takahashi, Kyoko; Ohta, Shigeru; Mashino, Tadahiko.

In: Toxicology Letters, Vol. 203, No. 1, 30.05.2011, p. 92-95.

Research output: Contribution to journalArticle

Nakamura, Shigeo ; Tezuka, Yoshito ; Ushiyama, Atsuko ; Kawashima, Chiaki ; Kitagawara, Yumina ; Takahashi, Kyoko ; Ohta, Shigeru ; Mashino, Tadahiko. / Ipso substitution of bisphenol A catalyzed by microsomal cytochrome P450 and enhancement of estrogenic activity. In: Toxicology Letters. 2011 ; Vol. 203, No. 1. pp. 92-95.
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