The Roles of MRP2, MRP3, OATP1B1, and OATP1B3 in Conjugated Hyperbilirubinemia

Abstract

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.

Evaluation of Cynomolgus Monkeys for the Identification of Endogenous Biomarkers for Hepatic Transporter Inhibition and as a Translatable Model to Predict Pharmacokinetic Interactions with Statins in Humans

“…For instance, in humans, unconjugated bilirubin is, at least in part, actively taken up into hepatocytes by OATP1B1 and OATP1B3, followed by glucuronidation by UGT1A1 to form conjugated bilirubin (monoglucuronosyl and bisglucuronosyl bilirubin), which is predominantly excreted into bile via multidrug resistance protein 2 (MRP2) (Keppler, 2014). Under conditions of cholestasis or inhibition of MRP2, the basolateral efflux transporter MRP3 transports bilirubin glucuronides into sinusoidal blood, where they are subsequently eliminated into the urine or retaken up into hepatocytes by OATP1B1 or OATP1B3.…”

Different Interaction Profiles of Direct-Acting Anti-Hepatitis C Virus Agents with Human Organic Anion Transporting Polypeptides

“…On the other hand, the functional inhibition of OATP1Bs is also believed to play an important role in hyperbilirubinemia induced by OATP1B inhibitors, such as rifamycin SV, CsA, and atazanavir (11). Further information about the roles of OATPs in DDIs and hyperbilirubinemia can be found elsewhere (10,16,17).…”

Screening to Identify Multidrug Resistance-Associated Protein Inhibitors with Neuroblastoma-Selective Cytotoxicity

“…29,30) Also, NSAIDs such as salicylate, piroxicam, ibuprofen, naproxen, sulindac, tolmetin, etodolac, dicrofenac, indomethacin, ketoprofen, phenylbutazone and celecoxib inhibit MRP1, MRP2 and/or MRP4. 30,31) MRP2 and MRP3 share 48% homology at the amino acid level, 32) and have several common inhibitors. 33) Thus, it is not unexpected that uricosuric drugs and NSAIDs also inhibit Mrp3 (Figs.…”