US EPA

1070213 

Journal Article 

Characterization of organic anion transporting polypeptide 1b2-null mice: essential role in hepatic uptake/toxicity of phalloidin and microcystin-LR 

Lu, H; Choudhuri, S; Ogura, K; Csanaky, IL; Lei, X; Cheng, X; Song, PZ; Klaassen, CD 

2008 

1 

Toxicological Sciences
ISSN: 1096-6080
EISSN: 1096-0929 

103 

1 

35-45 

English 

18296417 

10.1093/toxsci/kfn038 

WOS:000254955500005 

The liver-specific importer organic anion transporting polypeptide 1b2 (Oatp1b2, Slco1b2, 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 with wild-types, Oatp1b2-null mice had similar hepatic messenger RNA expression of most transporters examined except a higher Oatp1a4 but lower organic anion transporter 2. 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 with wild-type mice. In contrast, Oatp1b2-null mice were transiently protected from decrease in bile flow induced by estradiol-17beta-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 alpha-amanitin-induced hepatotoxicity compared with 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. 

Knockout; Liver; Mice; Microcystin; Oatp1b2; Phalloidin; alpha amanitin; bilirubin glucuronide; estradiol 17 glucuronide; messenger RNA; microcystin LR; organic anion transporter 1; organic anion transporter 1a4; organic anion transporter 1b2; organic anion transporter 2; phalloidin; phosphoprotein phosphatase 1; phosphoprotein phosphatase 2A; toxic substance; unclassified drug; animal experiment; animal tissue; article; bile flow; cholestasis; controlled study; enzyme binding; fluorescence analysis; gene expression regulation; homologous recombination; hyperbilirubinemia; knockout mouse; liver metabolism; liver toxicity; male; mouse; nonhuman; nucleotide sequence; phenotype; protein analysis; protein deficiency; protein function; wild type; Amino Acid Sequence; Animals; Base Sequence; Bile; DNA Primers; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microcystins; Molecular Sequence Data; Organic Anion Transporters; Phalloidine; Polymerase Chain Reaction; Basidiomycota; Chlorophyta; Mus