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

doi:10.1016/j.toxlet.2011.03.010

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

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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 language	English
Pages (from-to)	92-95
Number of pages	4
Journal	Toxicology Letters
Volume	203
Issue number	1
DOIs	https://doi.org/10.1016/j.toxlet.2011.03.010
Publication status	Published - 2011 May 30
Externally published	Yes

Keywords

Bisphenol A
Cytochrome P450
Estrogenic activity
Metabolic activation

ASJC Scopus subject areas

Toxicology

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10.1016/j.toxlet.2011.03.010

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title = "Ipso substitution of bisphenol A catalyzed by microsomal cytochrome P450 and enhancement of estrogenic activity",

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.",

keywords = "Bisphenol A, Cytochrome P450, Estrogenic activity, Metabolic activation",

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

note = "Funding Information: This study was supported in part by the “Open Research Center” Project for Private Universities, a matching fund subsidy from MEXT (Ministry of Education, Culture, Sports, Science, and Technology), 2007–2011.",

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doi = "10.1016/j.toxlet.2011.03.010",

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T1 - Ipso substitution of bisphenol A catalyzed by microsomal cytochrome P450 and enhancement of estrogenic activity

AU - Nakamura, Shigeo

AU - Tezuka, Yoshito

AU - Ushiyama, Atsuko

AU - Kawashima, Chiaki

AU - Kitagawara, Yumina

AU - Takahashi, Kyoko

AU - Ohta, Shigeru

AU - Mashino, Tadahiko

N1 - Funding Information: This study was supported in part by the “Open Research Center” Project for Private Universities, a matching fund subsidy from MEXT (Ministry of Education, Culture, Sports, Science, and Technology), 2007–2011.

PY - 2011/5/30

Y1 - 2011/5/30

N2 - 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.

AB - 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.

KW - Bisphenol A

KW - Cytochrome P450

KW - Estrogenic activity

KW - Metabolic activation

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

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