title: 17 beta-estradiol glucuronide: an inducer of cholestasis and a physiological substrate for the multidrug resistance transporter.
abstract: The multidrug resistance (MDR) gene family has been shown to be highly expressed in several normal tissues including the canalicular membrane of the hepatocyte. We report that a cholestatic estrogen metabolite, 17 beta-estradiol glucuronide (E217G), is a substrate for the MDR transporter, P-glycoprotein. In cytotoxicity studies, the MDR sarcoma cell line Dx5 was 4.7-fold resistant to E217G, and the K562/R7 leukemia MDR cell line was 5.0-fold resistant to E217G relative to their parental cell lines. There was also a 2- to 3-fold accumulation defect of [3H]E217G in the MDR cells relative to their parental cell lines. E217G (100 microM) modulated resistance ot doxorubicin, taxol, vinblastine, and etoposide in the Dx5 cells, completely reversing the 30- to 60-fold resistance observed with these agents. E217G had no effect on the toxicity of these compounds in the parental cell line (MES-SA). In contrast, MDR cells were not resistant to the noncholestatic estrogen metabolite, estriol 3-glucuronide, and this metabolite did not modulate resistance to MDR substrates. ATP-dependent transport of [3H]E217G in rat canalicular membranes was inhibited by several MDR substrates including vinblastine, etoposide, verapamil, cyclosporine, and PSC-833.
authors.affiliation: College of Pharmacy, University of Kentucky, Lexington 40356.
authors.forename: M
authors.initials: M
authors.lastname: Gosland
authors.forename: C
authors.initials: C
authors.lastname: Tsuboi
authors.forename: T
authors.initials: T
authors.lastname: Hoffman
authors.forename: S
authors.initials: S
authors.lastname: Goodin
authors.forename: M
authors.initials: M
authors.lastname: Vore
mesh_terms: D002779:Cholestasis / Q000139:chemically induced; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D004958:Estradiol / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism; D004964:Estriol / Q000031:analogs & derivatives; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D007951:Leukemia, Myeloid / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D012509:Sarcoma / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014747:Vinblastine / Q000494:pharmacology
chemical_list: C025483:estradiol-17 beta-glucuronide; C022810:estriol 3-glucuronide; D004958:Estradiol; D014747:Vinblastine; D005047:Etoposide; D004317:Doxorubicin; D004964:Estriol; D017239:Paclitaxel