RESUMO
Bisphenol A (BPA) is a widely used plasticizer whose estrogenic properties may impact hormone-responsive disorders and fetal development. In vivo, BPA appears to have greater activity than is suggested by its estrogen receptor (ER) binding affinity. This may be a result of BPA sulfation/desulfation providing a pathway for selective uptake into hormone-responsive cells. BPA is a substrate for estrogen sulfotransferase, and bisphenol A sulfate (BPAS) and disulfate are substrates for estrone sulfatase. Although the sulfated xenobiotics bind poorly to the ER, both stimulated the growth of receptor-positive breast tumor cells. Treatment of MCF-7 cells with BPAS leads to desulfation and uptake of BPA. No BPAS is found inside the cells. These findings suggest a mechanism for the selective uptake of BPA into cells expressing estrone sulfatase. Therefore, sulfation may increase the estrogenic potential of xenobiotics.
Assuntos
Neoplasias da Mama/metabolismo , Fenóis/farmacocinética , Sulfotransferases/efeitos dos fármacos , Óxidos de Enxofre/química , Ésteres do Ácido Sulfúrico/farmacocinética , Compostos Benzidrílicos , Sítios de Ligação , Catálise , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Humanos , Espectroscopia de Ressonância Magnética/métodos , Estrutura Molecular , Fenóis/síntese química , Fenóis/química , Receptores de Estrogênio/efeitos dos fármacos , Receptores de Estrogênio/metabolismo , Sensibilidade e Especificidade , Sulfotransferases/química , Sulfotransferases/metabolismo , Ésteres do Ácido Sulfúrico/síntese química , Ésteres do Ácido Sulfúrico/químicaRESUMO
The identification of an MCH R1 antagonist screening hit led to the optimization of a class of benzimidazole-based MCH R1 antagonists. Structure-activity relationships and efforts to optimize pharmacokinetic properties are detailed along with the demonstration of the effectiveness of an MCH R1 antagonist in an animal model of obesity.