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

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-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.

• Authors: Hong Lu, Supratim Choudhuri, Kenichiro Ogura, Iván L Csanaky, Xiaohong Lei, Xingguo Cheng, Pei-zhen Song, Curtis D Klaassen
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 103 Issue 1 Pg. 35-45 (May 2008) ISSN: 1096-0929 [Electronic] United States
• PMID: 18296417 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• DNA Primers
• Marine Toxins
• Microcystins
• Organic Anion Transporters
• Phalloidine
• cyanoginosin LR

Topics

• Amino Acid Sequence
• Animals
• Base Sequence
• Bile (metabolism)
• DNA Primers
• Liver (drug effects, metabolism)
• Male
• Marine Toxins
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Microcystins (pharmacokinetics, toxicity)
• Molecular Sequence Data
• Organic Anion Transporters (chemistry, genetics, physiology)
• Phalloidine (pharmacokinetics, toxicity)
• Polymerase Chain Reaction