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

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.