01/11/2009 - Reviews

Potentiation of MRP2/Mrp2-mediated estradiol-17beta-glucuronide transport by drugs--a concise review

K. Herédi Szabó, K. Jemnitz, E. Kis, E. Ioja, J. Jánossy, L. Vereczkey and P. Krajcsi

Chem Biodivers. 2009 Nov;6(11):1970-4.


MRP2/Mrp2 (ABCC2, cMOAT) is a member of the ABC transporter family, a group of proteins using the energy of ATP to transport molecules across cell membranes. MRP2/Mrp2 is expressed in various tissues, including the liver, the kidneys, and the intestine. The transporter is localized at the apical membrane of polarized epithelial cells in these tissues. Probably, its most important role is in the biliary elimination of various endogenous and exogenous anions. These anions are structurally diverse; they can be both conjugates and unconjugated anions. In 2003, two groups simultaneously found that estradiol-17b-glucuronide (E217bG) transport mediated by human MRP2 has positive cooperativity [1] [2]. These laboratories observed a rather sigmoid curve when investigating the concentration dependence of E217bG transport. This phenomenon is due to the existence of at least two binding sites of MRP2. The Hill number of the linearized saturation curves was > 1.5, confirming the presence of multiple binding sites. These sites can interact with each other, e.g., if a modulator compound binds to one of the sites, it is able to stimulate the transport of E217bG or other substrates. E217bG is a cholestatic endogenous estradiol metabolite, causing reversible, dose- dependent cholestasis [3]. The mechanism of E217bG-induced cholestasis is multi-factorial: it induces endocytic internalization of BSEP and MRP2 proteins 4] [5] and increases paracellular permeability [6]. In addition, E217bG inhibits the transport of bile salts by Bsep via trans-inhibition [7]. Transport by MRP2/Mrp2, thus, contributes to the cholestatic activity of E217bG, making this transport physiologically and pharmacologically even more important. In the present minireview, we give an overview of recent studies focusing on the interactions of MRP2/Mrp2 with E 2 17bG. The review is organized according to the experimental approaches used. In vitro – in vivo correlations (IVIVC) and species- specificity aspects will also be covered.

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