Abstract
Estradiol-17β-d-glucuronide (E2-17G) induces an acute but reversible inhibition of bile flow after its intravenous administration to rats, due in part to the endocytic retrieval of the canalicular multidrug resistance-associated transporter protein 2 and the bile salt export pump, transporters that contribute to bile flow. Decreased bile salt-independent bile flow (BSIF) is also involved and persists during the phase of recovery from cholestasis. Because glutathione and are major contributors to BSIF, we evaluated changes in their biliary excretion and the hepatic content of total glutathione during E2-17G-induced cholestasis. E2-17G acutely decreased bile flow and biliary excretion of total glutathione by about 80%; glutathione excretion was still inhibited at 80 min and 120 min, even though bile flow was partially and totally restored, respectively. Neither liver glutathione content nor the proportions of oxidized glutathione in bile and liver were affected by E2-17G at any time. concentrations in bile were unchanged, so that secretion paralleled variations in bile flow. In the isolated perfused liver, addition of E2-17G decreased both bile flow and the biliary concentration of glutathione, whereas addition of its noncholestatic isomer estradiol-3-d-glucuronide (E2-3G) did not inhibit bile flow, but significantly reduced the concentration of glutathione in bile. The bile:liver concentration ratios of glutathione were significantly decreased in vivo by E2-17G and in the perfused liver by E2-17G and E2-3G. These data indicate that E2-17G cis-inhibits the canalicular transport of glutathione and thus contributes to the cholestatic effect by inhibiting BSIF.
Footnotes
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This study was supported by U.S. Public Health Service Grant GM-55343 (to M.V.), and Consejo Nacional de Investigaciones Científicas y Técnicas, Agencia Nacional de Promoción Científica y Tecnológica, and Fundación Antorchas (to A.D.M.).
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ABBREVIATIONS: Bsep, bile salt export pump; BSDF, bile salt-dependent bile flow; BSIF, bile salt-independent bile flow; Mrp2, multidrug resistance-associated protein 2; GSSG, oxidized glutathione; GSH, reduced glutathione; AE2, anion exchanger 2; E2-17G, estradiol-17β-d-glucuronide; DNP-SG, dinitrophenyl-S-glutathione; E2-3G, estradiol-3-d-glucuronide; PE, polyethylene; GGT, γ-glutamyl transpeptidase; LDH, lactate dehydrogenase; IPRL, isolated perfused rat liver.
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DOI: 10.1124/jpet.103.054544.
- Received May 14, 2003.
- Accepted June 12, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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