Mrp2 is essential for estradiol-17beta(beta-D-glucuronide)-induced cholestasis in rats.

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Huang L, Smit JW, Meijer DK, Vore M

Mrp2 is essential for estradiol-17beta(beta-D-glucuronide)-induced cholestasis in rats.

Hepatology. 2000 Jul;32(1):66-72.

PubMed ID

10869290 [ View in PubMed

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Abstract

The present study evaluates the roles of the multidrug resistance-1 P-glycoprotein, Mdr1a/1b, the bile salt export pump (Bsep), and the multidrug resistance-associated protein-2 (Mrp2) in mediating cholestasis induced by estradiol-17beta(beta-D-glucuronide) (E(2)17G). Administration of inverted question mark(3)HE(2)17G (18 nmol/g body weight) gave a similar degree of cholestasis and biliary excretion of E(2)17G-equivalents in wild-type and Mdr1a(-/-)/1b(-/-) mice. When expressed in Sf9 cells, Bsep-mediated adenosine triphosphate (ATP)-dependent transport of taurocholate (TC, 1 micromol/L) in membrane vesicles was 110% +/- 12.5% and 108% +/- 17.3% of control in the presence of 10 and 50 micromol/L E(2)17G, respectively, whereas in rat canalicular membrane, both E(2)17G and the choleretic estradiol-3-beta-D-glucuronide (E(2)3G) inhibited ATP-dependent transport of TC to the same extent. Infusion of inverted question mark(3)HE(2)17G (24 micromol) did not induce cholestasis in Mrp2-deficient TR(-) rats whereas 2 micromol of inverted question mark(3)HE(2)17G inhibited bile flow by 51% in control Wistar rats. The maximal biliary concentration of E(2)17G was 3.5 and 2.5 mmol/L in control and TR(-) rats, respectively. However, 2.2 mmol/L of E(2)17G in bile is associated with inhibition of bile flow in control rats. These data show that (1) Mdr1a/1b are not essential for E(2)17G-mediated cholestasis, (2) direct inhibition of Bsep-mediated bile acid transport is not the mechanism for E(2)17G cholestasis, and (3) accumulation of E(2)17G in bile alone is not sufficient to induce cholestasis. These data indicate that the process of Mrp2-mediated transport of high concentrations of E(2)17G is essential for its induction of cholestasis.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Ethinylestradiol	Bile salt export pump	Protein	Humans	Unknown	Inhibitor	Details
Ethinylestradiol	P-glycoprotein 1	Protein	Humans	Unknown	Substrate	Details