17/3-EstradioI Glucuronide: An Inducer of Cholestasis and a Physiological Substrate for the Multidrug Resistance Transporter

Michael Gosland, Clifford Tsuboi, Tim Hoffman, Susan Goodin, Mary Vore

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    40 Scopus citations

    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, 170-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 μm) modulated resistance to doxorubicin, taxol, vinblastine, and etoposide in the Dx5 cells, completely reversing the 30- to 60-fold resistance observed with these agents. E2I7G 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]E2l7G in rat canalicular membranes was inhibited by several MDR substrates including vinblastine, etoposide, verapamil, cyclosporine, and PSC-833.

    Original languageEnglish (US)
    Pages (from-to)5382-5385
    Number of pages4
    JournalCancer Research
    Volume53
    Issue number22
    StatePublished - Nov 15 1993

    All Science Journal Classification (ASJC) codes

    • Oncology
    • Cancer Research

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