Increased concentrations of bilirubin glucuronides in blood plasma indicate 
hepatocellular dysfunction. Elucidation of the transport processes of bilirubin 
conjugates across the basolateral (sinusoidal) and the canalicular plasma 
membrane domains of hepatocytes has decisively contributed to our current 
understanding of the molecular basis of conjugated hyperbilirubinemia in human 
liver diseases. Under normal conditions, unconjugated bilirubin is taken up into 
hepatocytes by transporters of the organic anion-transporting polypeptide (OATP) 
family, followed by conjugation with glucuronic acid, and ATP-dependent 
transport into bile. This efflux across the canalicular membrane is mediated by 
multidrug resistance protein 2 (MRP2 or ABCC2), which is a 190-kDa glycoprotein 
transporting with high affinity and efficiency monoglucuronosyl bilirubin and 
bisglucuronosyl bilirubin into bile. MRP2 is hereditarily deficient in human 
Dubin-Johnson syndrome. Under pathophysiological conditions such as cholestatic 
liver injury and MRP2 inhibition, the basolateral efflux pump multidrug 
resistance protein 3 (MRP3 or ABCC3) is responsible for the occurrence of 
conjugated hyperbilirubinemia. MRP3 is a glycoprotein with a similar molecular 
mass as MRP2, with 48% amino acid identity, and with overlapping substrate 
specificity. Human MRP3 is the only basolateral efflux pump shown to transport 
bilirubin glucuronides. In human and rat hepatocytes, MRP3/Mrp3 is strongly 
upregulated under conditions of cholestasis and MRP2 deficiency. This is in line 
with the concept that basolateral efflux pumps of the hepatocyte compensate for 
impaired canalicular efflux of compounds into bile and contribute to balance the 
rate of uptake or synthesis of compounds in hepatocytes with the capacity for 
efflux into bile.