Characterization of Organic Anion Transporting Polypeptide 1b2-null Mice: Essential Role in Hepatic Uptake/Toxicity of Phalloidin and Microcystin-LR
Open Access
- 21 February 2008
- journal article
- research article
- Published by Oxford University Press (OUP) in Toxicological Sciences
- Vol. 103 (1), 35-45
- https://doi.org/10.1093/toxsci/kfn038
Abstract
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-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 α-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.Keywords
This publication has 49 references indexed in Scilit:
- Potent cytotoxicity of the phosphatase inhibitor microcystin LR and microcystin analogues in OATP1B1- and OATP1B3-expressing HeLa cellsMolecular Cancer Therapeutics, 2007
- SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acidPharmacogenetics and Genomics, 2006
- Evaluation of DNA microarray results with quantitative gene expression platformsNature Biotechnology, 2006
- Effect of SLCO1B1 genetic polymorphism on the pharmacokinetics of nateglinideBritish Journal of Clinical Pharmacology, 2006
- Analysis of the In Vivo Functions of Mrp3Molecular Pharmacology, 2005
- RAT AND MOUSE DIFFERENCES IN GENDER-PREDOMINANT EXPRESSION OF ORGANIC ANION TRANSPORTER (OAT1–3;SLC22A6–8) mRNA LEVELSPublished by American Society for Pharmacology & Experimental Therapeutics (ASPET) ,2004
- Cloning of the Full-Length Coding Sequence of Rat Liver-Specific Organic Anion Transporter-1 (rlst-1) and a Splice Variant and Partial Characterization of the Rat lst-1 GeneBiochemical and Biophysical Research Communications, 2000
- Full-Length cDNA Cloning and Genomic Organization of the Mouse Liver-Specific Organic Anion Transporter-1 (lst-1)Biochemical and Biophysical Research Communications, 2000
- Comparison of biliary excretion of organic anions in mice and ratsToxicology and Applied Pharmacology, 1982
- Dibromsulphalein (DBSP) Estimation of Hepatic Transport Function in Man*European Journal of Clinical Investigation, 1974