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

被引：71

作者：

Nakamura, Shigeo ^{[1
]}

Tezuka, Yoshito ^{[1
]}

Ushiyama, Atsuko ^{[1
]}

Kawashima, Chiaki ^{[1
]}

Kitagawara, Yumina ^{[1
]}

Takahashi, Kyoko ^{[1
]}

Ohta, Shigeru ^{[2
]}

Mashino, Tadahiko ^{[1
]}

机构：

[1] Keio Univ, Dept Pharmaceut Sci, Fac Pharm, Minato Ku, Tokyo 1058512, Japan

[2] Hiroshima Univ, Grad Sch Biomed Sci, Minami Ku, Hiroshima 7348551, Japan

来源：

TOXICOLOGY LETTERS | 2011年 / 203卷 / 01期

关键词：

Bisphenol A; Cytochrome P450; Estrogenic activity; Metabolic activation; OXYGEN-ATOM; METABOLIC PATHWAY; LIVER-MICROSOMES; DRUG-METABOLISM; MODEL SYSTEMS; PHENOLS; RAT; ELIMINATION;

D O I：

10.1016/j.toxlet.2011.03.010

中图分类号：

R99 [毒物学（毒理学）];

学科分类号：

100405 ;

摘要：

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 (18)O atom to HCA from H(2) (18)O 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. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

引用

页码：92 / 95

页数：4

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