MDR1 substrates/modulators protect against beta-estradiol-17beta-D-glucuronide cholestasis in rat liver.

Abstract

beta-Estradiol 17beta-D-glucuronide (E(2)17G), an endogenous cholestatic metabolite of estradiol, has been identified as a substrate for both hepatic P-glycoprotein (P-gp) and the multispecific organic anion transporter (MOAT), the liver-specific homologue of the multidrug resistance protein. The aim of the present studies was to determine the role of hepatic P-gp and MOAT in E(2)17G-mediated cholestasis and its biliary excretion using the isolated perfused rat liver. A bolus dose of E(2)17G (2 micromol) alone decreased the bile flow maximally from 1.5 to 0.3 microl/min/g liver. In the presence of an infusion of 1.5 microM daunorubicin or 1.0 microM Taxol, P-gp substrates, E(2)17G cholestasis was blocked such that 2 micromol E(2)17G decreased the bile flow from 1.48 to 1.31 or from 1.70 to 1.31 microl/min/g liver, respectively. In the presence of 1 and 3 microM Taxol, the log dose-response curves for E(2)17G cholestasis were shifted to the right 2-fold and 5-fold, respectively, in a parallel manner. Taxol (10 and 50 microM) inhibited the ATP-dependent transport of 10 microM E(2)17G in canalicular plasma membrane vesicles by 46 and 81%, respectively. Daunorubicin (1.5 microM) also shifted the log dose-response curve for E(2)17G cholestasis to the right about 4-fold. Neither Taxol nor daunorubicin decreased the biliary excretion of E(2)17G. Infusion of cyclosporine (6 microM), an inhibitor of both P-gp and MOAT, significantly blocked both E(2)17G cholestasis and biliary excretion, such that 16 micromol E(2)17G decreased the bile flow only 15-20%. In contrast, bromosulfophthalein, a MOAT substrate, had no effect on either E(2)17G-mediated cholestasis or its biliary excretion. These data indicate that P-gp plays an essential role in E(2)17G-mediated cholestasis and suggest that MOAT functions to deliver high concentrations of E(2)17G to P-gp.

• Authors: Y Liu, L Huang, T Hoffman, M Gosland, M Vore
• Journal: Cancer research (Cancer Res) Vol. 56 Issue 21 Pg. 4992-7 (Nov 01 1996) ISSN: 0008-5472 [Print] United States
• PMID: 8895755 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Anion Transport Proteins
• Carrier Proteins
• estradiol-17 beta-glucuronide
• Estradiol
• Cyclosporine
• Paclitaxel
• Daunorubicin

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (physiology)
• Animals
• Anion Transport Proteins
• Bile (drug effects)
• Carrier Proteins (physiology)
• Cholestasis (chemically induced, prevention & control)
• Chromatography, High Pressure Liquid
• Cyclosporine (pharmacology)
• Daunorubicin (pharmacology)
• Estradiol (analogs & derivatives, toxicity)
• Male
• Paclitaxel (pharmacology)
• Rats
• Rats, Sprague-Dawley