ToxSci Advance Access published online on February 21, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn038
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Characterization of Organic Anion Transporting Polypeptide 1b2-null Mice: Essential Role in Hepatic Uptake/Toxicity of Phalloidin and Microcystin-LR
* Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City KS, USA
Center for Food Safety and Nutrition, Food and Drug Administration, College Park, MD, USA
Department of Drug Metabolism and Molecular Toxicology, Tokyo University of Pharmacy and Life Science, Tokyo, Japan
1 To whom correspondence should be addressed at 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 December 20, 2007; revision received February 13, 2008; accepted February 15, 2008
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Abstract |
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The liver-specific importer organic anion transporting polypeptide 1b2 (Oatp1b2, Slc21a10, also known as Oatp4 and Lst-1) and its human orthologs OATP1B1/1B3 transport a large variety of chemicals. Oatp1b2-null mice were engineered by homologous recombination and their phenotype was characterized. Oatp1b2 protein was absent in livers of Oatp1b2-null mice. Oatp1b2-null mice develop normally and breed well. However, adult Oatp1b2-null mice had moderate conjugated hyperbilirubinemia. Compared to wild-types, Oatp1b2-null mice had similar hepatic mRNA expression of most transporters examined except a higher Oatp1a4 but lower organic anion transporter 2 (Oat2). Intra-arterial injection of the mushroom toxin phalloidin (an Oatp1b2-specific substrate identified in vitro) caused cholestasis in wild-type mice but not in Oatp1b2-null mice. Hepatic uptake of fluorescence-labeled phalloidin was absent in Oatp1b2-null mice. Three hours after administration of microcystin-LR (a blue-green algae toxin), the binding of microcystin-LR to hepatic protein phosphatase 1/2a was much lower in Oatp1b2-null mice compared to wild-type mice. In contrast, Oatp1b2-null mice were transiently protected from decrease in bile flow induced by estradiol-17β-D-glucuronide, a common substrate for Oatps. Oatp1b2-null mice were completely resistant to the hepatotoxicity induced by phalloidin and microcystin-LR, but were similarly sensitive to 
-amanitin-induced hepatotoxicity compared to wild-type mice. In conclusion, Oatp1b2-null mice display altered basic physiology and markedly decreased hepatic uptake/toxicity of phalloidin and microcystin-LR. Oatp1b2-null mice are useful in elucidating the role of Oatp1b2 and its human orthologs OATP1B1/1B3 in hepatic uptake and systemic disposition of toxic chemicals and therapeutic drugs.
Key Words: Oatp1b2; liver; knockout; mice; phalloidin; microcystin.
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