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J. Biol. Chem., Vol. 276, Issue 26, 23492-23498, June 29, 2001

This Article Full Text Full Text (PDF) All Versions of this Article: 276/26/23492    most recent M102494200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend 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 Battaglia, E. Articles by Gollan, J. Search for Related Content PubMed PubMed Citation Articles by Battaglia, E. Articles by Gollan, J. Social Bookmarking                      What's this?

A Unique Multifunctional Transporter Translocates Estradiol-17-Glucuronide in Rat Liver Microsomal Vesicles^*

Eric Battaglia^§¶ and John Gollan

From the  Gastroenterology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, the ^§ Laboratoire d' Ingénierie Moléculaire et Biochimie Pharmacologique, UFR SciFA, Metz, France, and the  Department of Medicine, Adelaide University, Royal Adelaide Hospital, Adelaide 5000, South Australia

A wide array of drugs, xenobiotics, and endogenous compounds undergo detoxification by conjugation with glucuronic acid in the liver via the action of UDP-glucuronosyltransferases. The mechanism whereby glucuronides, generated by this enzyme system in the lumen of the endoplasmic reticulum (ER), are exported to the cytosol prior to excretion is unknown. We examined this process in purified rat liver microsomes using a rapid filtration technique and [³H]estradiol-17-D-glucuronide ([³H]E₂17G) as model substrate. Time-dependent uptake of intact [³H]E₂17G was observed and shrinkage of ER vesicles by raffinose lowered the steady-state level of [³H]E₂17G accumulation. In addition, rapid efflux of [³H]E₂17G from rat liver microsomal vesicles suggested that the transport process is bidirectional. Microsomal uptake was saturable with an apparent K_m and V_max of 3.29 ± 0.58 µM and 0.19 ± 0.02 nmol·min¹·mg protein¹, respectively. Transport of [³H]E₂17G was inhibited by the anion transport inhibitors 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid and probenecid. Specificity of the transport process was investigated by studying the cis-inhibitory effect of anionic metabolites, as well as substrates of the plasma membrane multidrug resistance-associated proteins on the uptake of [³H]E₂17G. Collectively, these data are indicative of a novel multifunctional and bidirectional protein carrier for E₂17G and other anionic compounds in the hepatic ER. This intracellular membrane transporter may contribute to the phenomenon of multidrug resistance.

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