Characterization of organic anion transporting polypeptide 1b2-null mice: essential role in hepatic uptake/toxicity of phalloidin and microcystin-LR.
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.
Lu
Hong
H
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160-7417, USA.
Choudhuri
Supratim
S
Ogura
Kenichiro
K
Csanaky
Iván L
IL
Lei
Xiaohong
X
Cheng
Xingguo
X
Song
Pei-zhen
PZ
Klaassen
Curtis D
CD
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001646:Bile / Q000378:metabolism; D017931:DNA Primers; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008387:Marine Toxins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052998:Microcystins / Q000493:pharmacokinetics* / Q000633:toxicity*; D008969:Molecular Sequence Data; D027361:Organic Anion Transporters / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D010590:Phalloidine / Q000493:pharmacokinetics* / Q000633:toxicity*; D016133:Polymerase Chain Reaction
D017931:DNA Primers; D008387:Marine Toxins; D052998:Microcystins; D027361:Organic Anion Transporters; D010590:Phalloidine; C057862:cyanoginosin LR