This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gosland, M. Articles by Vore, M. Search for Related Content PubMed PubMed Citation Articles by Gosland, M. Articles by Vore, M.

17ß-Estradiol Glucuronide: An Inducer of Cholestasis and a Physiological Substrate for the Multidrug Resistance Transporter¹

College of Pharmacy [M. G., C. T., S. G.] and the Department of Pharmacology, College of Medicine [T. H., M. V.], University of Kentucky, Lexington, Kentucky 40356

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, 17ß-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. 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.

¹ Supported in part by Grant IN-163 from the American Cancer Society and USPHS Grant HD13250.

² To whom requests for reprints should be addressed, at Lucille P. Markey Cancer Center, University of Kentucky, 800 Rose Street, Room CC-405, Lexington, KY 40356-0093.

Received 8/17/93. Accepted 10/ 5/93.

This article has been cited by other articles:

				R. M. Roman, Y. Wang, S. D. Lidofsky, A. P. Feranchak, N. Lomri, B. F. Scharschmidt, and J. G. Fitz Hepatocellular ATP-binding Cassette Protein Expression Enhances ATP Release and Autocrine Regulation of Cell Volume J. Biol. Chem., August 29, 1997; 272(35): 21970 - 21976. [Abstract] [Full Text] [PDF]

				D. W. Loe, K. C. Almquist, S. P. C. Cole, and R. G. Deeley ATP-dependent 17beta-Estradiol 17-(beta-D-Glucuronide) Transport by Multidrug Resistance Protein (MRP) J. Biol. Chem., April 19, 1996; 271(16): 9683 - 9689. [Abstract] [Full Text] [PDF]