HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver.

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 Rotor-syndrome 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.
AuthorsEvita van de Steeg, Viktor Stránecký, Hana Hartmannová, Lenka Nosková, Martin Hřebíček, Els Wagenaar, Anita van Esch, Dirk R de Waart, Ronald P J Oude Elferink, Kathryn E Kenworthy, Eva Sticová, Mohammad al-Edreesi, A S Knisely, Stanislav Kmoch, Milan Jirsa, Alfred H Schinkel
JournalThe Journal of clinical investigation (J Clin Invest) Vol. 122 Issue 2 Pg. 519-28 (Feb 2012) ISSN: 1558-8238 [Electronic] United States
PMID22232210 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Liver-Specific Organic Anion Transporter 1
  • Organic Anion Transporters
  • Organic Anion Transporters, Sodium-Independent
  • SLCO1B1 protein, human
  • SLCO1B3 protein, human
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • bilirubin glucuronate
  • Bilirubin
Topics
  • Animals
  • Bilirubin (analogs & derivatives, metabolism)
  • DNA Mutational Analysis
  • Female
  • Humans
  • Hyperbilirubinemia, Hereditary (blood, genetics, physiopathology)
  • Liver (metabolism)
  • Liver-Specific Organic Anion Transporter 1
  • Male
  • Mice
  • Mice, Knockout
  • Organic Anion Transporters (deficiency, genetics)
  • Organic Anion Transporters, Sodium-Independent (deficiency, genetics)
  • Pedigree
  • Solute Carrier Organic Anion Transporter Family Member 1B3

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: