Skip to main content
Log in

Biliary Excretion of 17β-Estradiol 17β-d-Glucuronide Is Predominantly Mediated by cMOAT/MRP2

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose. The mechanism for the biliary excretion of 17β-estradiol17β0-d-glucuronide (E217βG), a cholestatic metabolite of estradiol, isstill controversial. The purpose of the present study is to examine thetransport of E217βG across the bile canalicular membrane.

Methods. We examined the uptake of [3H]E217βG by isolatedcanalicular membrane vesicles (CMVs) prepared from Sprague-Dawley (SD)rats and Eisai Hyperbilirubinemic rats (EHBR) whose canalicularmultispecific organic anion transporter/multidrug resistance associatedprotein 2 (cMOAT/MRP2) function is hereditarily defective. Also,in vivo biliary excretion of intravenously administered [3H]E217βGwas examined.

Results. In CMVs prepared from SD rats, but not from EHBR, amarked ATP-dependent uptake of [3H]E217βG was observed.Moreover, E217βG competitively inhibited the ATP-dependent uptake of[3H]2,4-dinitrophenyl-S-glutathione (DNP-SG). In addition, nosignificant inhibitory effect of verapamil (100 μM) and PSC-833 (5 μM) onthe uptake of [3H]E217βG was observed. In vivo, the biliary excretionof intravenously administered [3H]E217βG was severely impaired inEHBR while the biliary excretion of [3H]E217βG in SD rats wasreduced by administering a cholestatic dose (10 μmol/kg) unlabeledE217βG, but not by PSC-833 (3 mg/kg).

Conclusions. The transport of E217βG across the bile canalicularmembrane is predominantly mediated by cMOAT/MRP2.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. M. Vore, Y. Liu, and L. Huang. Cholestatic properties and hepatic transport of steroid glucuronides. Drug. Metab. Rev. 29:183–203 (1997).

    Google Scholar 

  2. R. Bossard, B. Stieger, B. O'Neill, G. Fricker, and P. J. Meier. Ethinylestradiol treatment induces multiple canalicular membrane transport alterations in rat liver. J. Clin. Invest. 91:2714–2720 (1993).

    Google Scholar 

  3. M. Trauner, M. Arrese, C. J. Soroka, M. Ananthanarayanan, T. A. Koeppel, S. F. Schlosser, F. J. Suchy, D. Keppler, and J. L. Boyer. The rat canalicular conjugate export pump (Mrp2) is downregulated in intrahepatic and obstructive cholestasis. Gastroenterol. 113:255–264 (1997).

    Google Scholar 

  4. N. R. Koopen, H. Wolters, R. Havinga, R. J. Vonk, P. L. M. Jansen, and M. Müller. Impaired activity of the bile canalicular organic anion transporter (Mrp2/cmoat) is not main cause of ethinylestradiol-induced cholestasis in the rat. Hepatol. 27:537–545 (1998).

    Google Scholar 

  5. B. Stieger and P. J. Meier. Bile acid and xenobiotic transporters in liver. Curr. Opin. Cell. Biol. 10:462–467 (1998).

    Google Scholar 

  6. H. Kouzuki, H. Suzuki, K. Ito, R. Ohashi, and Y. Sugiyama. Contribution of organic anion transporting polypeptide to uptake of its possible-substrates into rat hepatocyte. J. Pharmacol. Exp. Ther. 288:627–634 (1999).

    Google Scholar 

  7. L. Li, T. K. Lee, P. J. Meier, and N. Ballatori. Identification of glutathione as a driving force and leukotriene C4 as a substrate for oatp1, the hepatic sinusoidal organic solute transporter. J. Biol. Chem. 273:16184–16191 (1998).

    Google Scholar 

  8. R. P. Oude Elferink, D. K. Meijer, F. Kuipers, P. L. Jansen, A. K. Groen, and G. M. Groothuis. Hepatobiliary secretion of organic compounds; molecular mechanisms of membrane transport. Biochim. Biophys. Acta. 1241:215–268 (1995).

    Google Scholar 

  9. D. Keppler and J. Konig. Hepatic canalicular membrane 5: Expression and localization of the conjugate export pump encoded by the MRP2 (cMRP/cMOAT) gene in liver. FASEB. J. 11:509–516 (1997).

    Google Scholar 

  10. H. Kusuhara, H. Suzuki, and Y. Sugiyama. The role of P-glycoprotein and canalicular multispecific organic anion transporter (cMOAT) in the hepatobiliary excretion of drugs. J. Pharm. Sci. 87:1025–1040 (1998).

    Google Scholar 

  11. H. Suzuki and Y. Sugiyama. Excretion of GSSG and glutathione conjugates mediated by MRP1 and cMOAT/MRP2. Semin. Liv. Dis. 18:359–376 (1998).

    Google Scholar 

  12. H. Takikawa, R. Yamazaki, N. Sano, and M. Yamanaka. Biliary excretion of estradiol-17β-glucuronide in the rat. Hepatol. 23:607–613 (1996).

    Google Scholar 

  13. K. Ito, H. Suzuki, T. Hirohashi, K. Kume, T. Shimizu, and Y. Sugiyama. Molecular cloning of canalicular multispecific organic anion transporter defective in Eisai hyperbilirubinemic rats. Am. J. Physiol. 35:G16–G22 (1997).

    Google Scholar 

  14. M. Büchler, J. Konig, M. Brom, J. Kartenbeck, H Spring, T. Horie, and D Keppler. cDNA cloning of the hepatocyte canalicular isoform of the multidrug resistance protein, cMrp, reveals a novel conjugate export pump deficient in hyperbilirubinemic mutant rats. J. Biol. Chem. 271:15091–15098 (1996).

    Google Scholar 

  15. D. Lautier, Y. Canitrot, R. G. Deeley, and S. P. Cole. Multidrug resistance mediated by the multidrug resistance protein (MRP) gene. Biochem. Pharmacol. 52:967–977 (1996).

    Google Scholar 

  16. D. W. Loe, R. G. Deeley, and S. P. Cole. Biology of the multidrug resistance-associated protein, MRP. Eur. J. Cancer. 32:945–57 (1996).

    Google Scholar 

  17. M. Vore, T. Hoffman, and M. Gosland. ATP-dependent transport of β-estradiol 17-(β-D-glucuronide) in rat canalicular membrane vesicles. Am. J. Physiol. 271:G791–798 (1996).

    Google Scholar 

  18. L. Huang, T. Hoffmann, and M. Vore. Adenosine triphosphate-dependent transport of estradiol-17β (b-D-glucuronide) in membrane vesicles by MDR1 expressed in insect cells. Hepatol. 28:1371–1377 (1998).

    Google Scholar 

  19. K. Kobayashi, Y. Sogame, H. Hara, and K. Hayashi. Mechanism of glutathione S-conjugate transport in canalicular and basolateral rat liver plasma membranes. J. Biol. Chem. 265:7737–7741 (1990).

    Google Scholar 

  20. K. Niinuma, O. Takenaka, T. Horie, K. Kobayashi, Y. Kato, H. Suzuki, and Y. Sugiyama. kinetic analysis of the primary active transport of conjugated metabolites across the bile canalicular membrane: comparative study of S-(2,4-Dinitrophenyl)-glutathione and 6-Hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole glucuronide. J. Pharmacol. Exp. Ther. 282:866–872 (1997).

    Google Scholar 

  21. M. Böhme, M. Büchler, M. Müller, and D. Keppler. Differential inhibition by cyclosporins of primary active ATP-dependent transporters in the hepatocyte canalicular membrane. FEBS. Lett. 333:193–196 (1993).

    Google Scholar 

  22. Y. Kamimoto, Z. Gatmaitan, J. Hsu, and I. M. Arias. The function of Gp170, the multidrug resistance gene product, in rat liver canalicular membrane vesicles. J. Biol. Chem. 264:11693–11698 (1989).

    Google Scholar 

  23. T. Yamada, Y. Kato, H. Kusuhara, M. Lemaire, and Y. Sugiyama Characterization of the transport of a cationic octapeptide, octreotide, in rat bile canalicular membrane: possible involvement of P-glycoprotein. Biol. Pharm. Bull. 21:874–878 (1998).

    Google Scholar 

  24. S. Song, H. Suzuki, R. Kawai, and Y. Sugiyama. Effect of PSC 833, a P-glycoprotein modulator, on the disposition of vincristine and digoxin in rats. Drug. Metab. Dispos. 27:689–94 (1999).

    Google Scholar 

  25. T. Hirohashi, H. Suzuki, K. Ito, K. Kume, T. Shimizu, and Y. Sugiyama. Hepatic expression of multidrug resistance-associated protein (MRP)-like proteins maintained in Eisai hyper-bilirubinemic rats (EHBR). Mol. Pharmacol. 53:1068–1075 (1998).

    Google Scholar 

  26. T. Hirohashi, H. Suzuki, and Y. Sugiyama. Characterization of the transport properties of cloned rat multidrug resistance associated protein 3 (MRP3). J. Biol. Chem. 274:15181–15185 (1999).

    Google Scholar 

  27. J. Konig, D. Rost, Y. Cui, and D. Keppler. Characterization of the human multidrug resistance protein isoform MRP3 localized to the basolateral hepatocyte membrane. Hepatol. 29:1156–1163 (1999).

    Google Scholar 

  28. M. Kool, M. van der Linden, M. de Haas, G. L. Scheffer, J. M. L. de Vree, A. J. Smith, G. Jansen, G. J. Peters, N. Ponne, R. J. Scheper, R. P. J. Oude Elferink, F. Baas, and P. Borst. MRP3, an organic anion transporter able to transport anti-cancer drugs. Proc. Natl. Acad. Sci. 96:6914–6919 (1999).

    Google Scholar 

  29. B. Stieger, K. Fattinger, J. Madon, G. A. Kullak-Ublick, and P. J. Meier. Drug-and estrogen-induced cholestasis through inhibition of the hepatocellular Bile salt export pump (Bsep) of rat liver. Gastroenterol. 118:422–430 (2000).

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Morikawa, A., Goto, Y., Suzuki, H. et al. Biliary Excretion of 17β-Estradiol 17β-d-Glucuronide Is Predominantly Mediated by cMOAT/MRP2. Pharm Res 17, 546–552 (2000). https://doi.org/10.1023/A:1026412915168

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1026412915168

Navigation