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ToxSci Advance Access first published online on February 26, 2009
This version published online on April 15, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp045
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Nrf2 Activation Enhances Biliary Excretion of Sulfobromophthalein by Inducing Glutathione-S-Transferase Activity

Scott A. Reisman, Iván L. Csanaky, Ronnie L. Yeager and Curtis D. Klaassen

Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160

Corresponding Author: Curtis D. Klaassen, Ph.D., Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd. Kansas City, KS 66160-7417, USA. Phone: (913)588-7500, Fax: (913) 588-7501, E-mail: cklaasse{at}kumc.edu

Received January 12, 2009; revision received February 19, 2009; accepted February 20, 2009


  Abstract

Sulfobromophthalein (BSP) is used to study hepatobiliary excretory function. BSP is conjugated with glutathione (GSH), whereas its dibrominated analog disulfobromophthalein (DBSP) is not conjugated with GSH prior to biliary excretion. In addition, both BSP and DBSP are transported into hepatocytes via organic anion transporting polypeptides (Oatps) and excreted into bile via multidrug resistance-associated protein 2 (Mrp2). Nrf2 is a transcription factor that under basal conditions is targeted for proteasomal degradation in the cytosol by Keap1. Electrophilic and oxidative stress facilitate Nrf2 nuclear translocation and subsequent induction of cytoprotective genes, including GSH-synthetic enzymes, GSH-S-transferases (Gsts), and Mrp transporters. The current study determined whether varying the amount of Nrf2 activation would effect the elimination of BSP and DBSP. Male wild-type (WT), Nrf2-null, and Keap1-knockdown (Keap1-kd) mice were administered BSP or DBSP. Within 30 min, Nrf2-null mice excreted 25%, WT mice 52%, and Keap1-kd mice 80% of the injected BSP. Liver GSH content was not altered by BSP. The biliary excretion of GSH and mRNA expression of major Gsts were directly proportional to the amount of Nrf2. Moreover, BSP-GSH conjugation activity in the liver of Nrf2-null and Keap1-kd mice was 42 and 237% of WT mice, respectively. In contrast to BSP, there were no differences in biliary excretion or plasma disappearance of DBSP among the three genotypes, suggesting that the modest differences in Mrp2 mRNA expression among genotypes do not affect BSP or DBSP biliary excretion. Collectively, these results indicate that increased biliary excretion of BSP, and possibly other compounds, is due to Nrf2-induced Gst mRNA expression and enzyme activity.

Key Words: Nrf2; Gsts; BSP, biliary excretion.


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