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ToxSci Advance Access published online on April 30, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp094
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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

Compensatory Induction of Liver Efflux Transporters in Response to ANIT-Induced Liver Injury is Impaired in FXR-null Mice

Yue Julia Cui1, Lauren M Aleksunes1, Yuji Tanaka1, Michael J Goedken2 and Curtis D Klaassen1,*

1 University of Kansas Medical Center, Department of Pharmacology, Toxicology and Therapeutics, Kansas City, KS 2 Department of Pathology, Schering-Plough Research Institute, Lafayette, NJ

* To whom correspondence should be addressed: Curtis D. Klaassen, PhD, Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160 USA, OFFICE: 913-588-7500 FAX: 913-588-7501, Email address: cklaasse{at}kumc.edu (C.D. Klaassen)

Received March 4, 2009; revision received April 23, 2009; accepted April 24, 2009


  Abstract

Alpha-naphthyl isothiocyanate (ANIT) is a hepatotoxicant that produces acute intrahepatic cholestasis in rodents. FXR and PXR are two major bile-acid sensors in liver. The purpose of this study was to characterize the regulation of hepatic transporters by FXR and PXR during ANIT-induced liver injury. Wild-type, FXR-null, and PXR-null mice were administered ANIT (75 mg/kg, po) and evaluated 48h later for hepatotoxicity and mRNA expression of basolateral uptake (Ntcp, Oatp1a1, Oatp1a4, Oatp1b2) and efflux transporters (Ost{alpha}, Ostβ, Mrp3, Mrp4), as well as canalicular transporters (Bsep, Mrp2, Mdr2, Atp8b1). Livers from wild-type and PXR-null mice had comparable multifocal necrosis 48h after ANIT. However, ANIT-treated FXR-null mice have fewer and smaller necrotic foci than wild-type mice, but had scattered single-cell hepatocyte necrosis throughout the liver. Serum alanine transaminase, alkaline phosphatase (ALP), and direct bilirubin were increased in all genotypes, with higher ALP levels in FXR-null mice. Serum and liver unconjugated bile acids were higher in ANIT-treated FXR-null mice than the other two genotypes. ANIT induced mRNA expression of Mdr2, Bsep, and Atp8b1 in wild-type and PXR-null mice, but failed to up-regulate these genes in FXR-null mice. mRNA expression of uptake transporters declined in livers of all genotypes following ANIT treatment. ANIT increased Ostβ and Mrp3 mRNA in livers of wild-type and PXR-null mice, but did not alter Ostβ mRNA in FXR-null mice. In conclusion, FXR deficiency enhances susceptibility of mice to ANIT-induced liver injury, likely a result of impaired induction of hepatobiliary efflux transporters and subsequent hepatic accumulation of unconjugated bile acids.

Key Words: ANIT; FXR; PXR; transporters; bile acids; liver.


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