Mrp2 is essential for estradiol‐17β(β‐ D ‐glucuronide)–induced cholestasis in rats

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‐17β(β‐ d ‐glucuronide) (E 2 17G). Administration of [ 3 H]E 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 μmol/L) in membrane vesicles was 110% ± 12.5% and 108% ± 17.3% of control in the presence of 10 and 50 μmol/L E 2 17G, respectively, whereas in rat canalicular membrane, both E 2 17G and the choleretic estradiol‐3‐β‐ d ‐glucuronide (E 2 3G) inhibited ATP‐dependent transport of TC to the same extent. Infusion of [ 3 H]E 2 17G (24 μmol) did not induce cholestasis in Mrp2‐deficient TR − rats whereas 2 μmol of [ 3 H]E 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.