Print Email Facebook Twitter Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver Title Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver Author van de Steeg, E. Stránecký, V. Hartmannová, H. Nosková, L. Hrebícek, M. Wagenaar, E. van Esch, A. de Waart, D.R. Oude Elferink, R.P.J. Kenworthy, K.E. Sticová, E. Al-Edreesi, M. Knisely, A.S. Kmoch, S. Milan Jirsa, M. Schinkel, A.H. Publication year 2012 Abstract Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotorsyndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane. OATP1B1 polymorphisms have previously been linked to drug hypersensitivities. Using mice deficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b transporters mediate their hepatic reuptake. Transgenic expression of human OATP1B1 or OATP1B3 restored the function of this detoxification-enhancing liver-blood shuttle in Oatp1a/1b-deficient mice. Within liver lobules, this shuttle may allow flexible transfer of bilirubin conjugates (and probably also drug conjugates) formed in upstream hepatocytes to downstream hepatocytes, thereby preventing local saturation of further detoxification processes and hepatocyte toxic injury. Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia. Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks. Subject LifePHS - Pharmacokinetics & Human StudiesEELS - Earth, Environmental and Life SciencesFood and NutritionBiologyHealthy Living To reference this document use: http://resolver.tudelft.nl/uuid:a5c7ebc7-8713-4827-88ef-6302cefc4db4 DOI https://doi.org/10.1172/jci59526 TNO identifier 462630 Source Journal of Clinical Investigation, 2012 (122), 519-528 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.