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ANIT-induced intrahepatic cholestasis alters hepatobiliary transporter expression via Nrf2-dependent and independent

Yuji Tanaka1, Lauren M Aleksunes, Yue Julia Cui

  • 1Department of Pharmacology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.

Toxicological Sciences : an Official Journal of the Society of Toxicology
|February 3, 2009
PubMed

Insights

Mice lacking Nrf2 showed similar liver injury from ANIT, but altered bile acid transporters, suggesting Nrf2 activation may treat cholestasis.

Area of Science:

  • Hepatology
  • Toxicology
  • Molecular Biology

Background:

  • Alpha-naphthylisothiocyanate (ANIT) induces intrahepatic cholestasis by damaging biliary epithelial cells.
  • Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates hepatobiliary transporters and may influence cholestasis adaptation.
  • This study investigates the role of Nrf2 in ANIT-induced liver injury and transporter regulation.

Purpose of the Study:

  • To determine if ANIT-induced hepatotoxicity and hepatobiliary transporter expression are altered in Nrf2-null mice.
  • To elucidate the compensatory mechanisms in Nrf2-deficient mice during ANIT-induced cholestasis.

Main Methods:

  • Wild-type and Nrf2-null mice were administered ANIT (75 mg/kg).
  • Hepatotoxicity was assessed at 48 hours.
  • Serum and liver bile acid levels were measured.
  • mRNA expression of key transporters (Bsep, Mdr2, Mrp3, Ntcp, Oatp1b2) and regulatory factors (SHP, HNF1alpha) was analyzed.

Main Results:

  • ANIT-induced hepatotoxicity was similar in wild-type and Nrf2-null mice at 48 hours.
  • Nrf2-null mice had lower serum and liver bile acid accumulation post-ANIT.
  • ANIT upregulated efflux transporters (Bsep, Mdr2, Mrp3) in wild-type but not Nrf2-null mice.
  • Uptake transporters (Ntcp, Oatp1b2) decreased in both genotypes, with greater decline in Nrf2-null mice.
  • SHP expression increased, and HNF1alpha downregulated in Nrf2-null mice after ANIT.

Conclusions:

  • Nrf2-null mice exhibit compensatory changes, including altered transporter expression, limiting ANIT toxicity.
  • Upregulation of SHP and downregulation of HNF1alpha and uptake transporters contribute to similar injury levels despite Nrf2 absence.
  • Pharmacological activation of Nrf2 may offer a therapeutic strategy for intrahepatic cholestasis.

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