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.