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.
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Nakamura
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Tezuka
authors.forename: Atsuko
authors.initials: A
authors.lastname: Ushiyama
authors.forename: Chiaki
authors.initials: C
authors.lastname: Kawashima
authors.forename: Yumina
authors.initials: Y
authors.lastname: Kitagawara
authors.forename: Kyoko
authors.initials: K
authors.lastname: Takahashi
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ohta
authors.forename: Tadahiko
authors.initials: T
authors.lastname: Mashino
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds; D001665:Binding Sites; D001711:Biotransformation; D045744:Cell Line, Tumor; D052244:Endocrine Disruptors / Q000378:metabolism* / Q000494:pharmacology; D004968:Estrogens, Non-Steroidal / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D006873:Hydroquinones / Q000378:metabolism; D007527:Isoenzymes; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D010636:Phenols / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020218:Response Elements / Q000187:drug effects; D014162:Transfection; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D052244:Endocrine Disruptors; D004968:Estrogens, Non-Steroidal; D006873:Hydroquinones; D007527:Isoenzymes; D010636:Phenols; C006780:bisphenol A; D000098826:Bisphenol A Compounds; C031927:hydroquinone