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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 OATPlBl and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane. OATPlBl polymorphisms have previously been linked to drug hypersensitivities. Using mice deficient in Oatpla/lb and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatpla/lb transporters mediate their hepatic reuptake. Transgenic expression of human OATPlBl or OATP1B3 restored the function of this detoxification-enhancing liver-blood shuttle in Oatp la/ lb-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.
Introduction
Rotor syndrome (RS; OMIM %237450) is a rare, benign hereditary conjugated hyperbilirubinemia, also featuring coproporphyrinuria and strongly reduced liver uptake of many diagnostic compounds, including cholescintigraphic tracers ( 1 -6). RS is an autosomal recessive disorder that clinically resembles another conjugated hyperbilirubinemia, the Dubin-Johnson syndrome (DJS; OMIM #237500) (7, 8). In both RS and DJS, mild jaundice begins shortly after birth or in childhood. There are no signs of hemolysis, and routine hematologic and clinical-biochemistry test results are mal, aside from the primarily conjugated hyperbilirubinemia. RS is, however, distinguishable from DJS by several criteria (1, 2, 9, 10): (a) it lacks the hepatocyte pigment deposits typical of DJS; (b) in RS, but nor DJS, there is delayed plasma clearance of unconjugated bromsulphthalein (BSP), an anionic diagnostic dye, and...