17-BETA-ESTRADIOL GLUCURONIDE - AN INDUCER OF CHOLESTASIS AND A PHYSIOLOGICAL SUBSTRATE FOR THE MULTIDRUG-RESISTANCE TRANSPORTER

The multidrug resistance (MDR) gene family has been shown to be highly expressed in several normal tissues including the canalicular membran e of the hepatocyte. We report that a cholestatic estrogen metabolite, 17beta-estradiol glucuronide (E(2)17G), is a substrate for the MDR tr ansporter, P-glycoprotein. In cytotoxicity studies, the MDR sarcoma ce ll line Dx5 was 4.7-fold resistant to E(2)17G, and the K562/R7 leukemi a MDR cell line was 5.0-fold resistant to E(2)17G relative to their pa rental cell lines. There was also a 2- to 3-fold accumulation defect o f [H-3]E(2)17G in the MDR cells relative to their parental cell lines. E(2)17G (100 muM) modulated resistance to doxorubicin, taxol, vinblas tine, and etoposide in the Dx5 cells, completely reversing the 30- to 60-fold resistance observed with these agents. E(2)17G had no effect o n the toxicity of these compounds in the parental cell line (MES-SA). In contrast, MdR cells were not resistant to the noncholestatic estrog en metabolite, estriol 3-glucuronide, and this metabolite did not modu late resistance to MDR substrates. ATP-dependent transport of [H-3]E(2 )17G in rat canalicular membranes was inhibited by several MDR substra tes including vinblastine, etoposide, verapamil, cyclosporine, and PSC -833.