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 re uptake. 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.