Quick Definition
What is MRP2 (Multidrug Resistance-Associated Protein 2 / ABCC2)?: MRP2 (ABCC2, cMOAT) is an ABC efflux transporter on the canalicular membrane of hepatocytes that exports organic anions, glucuronide and sulfate conjugates, glutathione conjugates, and bile salts into bile. MRP2 inhibition reduces biliary excretion of these substrates, contributing to intrahepatic cholestasis and drug-induced liver injury.
Why BSEP and MRP2 are often assessed together
BSEP and MRP2 work in concert on the hepatocyte canalicular membrane. Many cholestatic drugs inhibit both simultaneously — clinical severity of cholestatic DILI correlates with combined BSEP + MRP2 inhibition. Adding MRP2 to the BSEP vesicle panel is practical and cost-effective: identical assay format, similar incubation conditions, and more informative result than BSEP alone.
MRP2 and Dubin-Johnson syndrome
Genetic MRP2 deficiency (Dubin-Johnson syndrome) causes conjugated hyperbilirubinemia without symptoms — the benign clinical phenotype helps validate MRP2 as a relevant DDI target and explains why some drugs cause drug-induced conjugated hyperbilirubinemia without full cholestatic DILI.
Key Facts
- Located on the canalicular membrane of hepatocytes — the same membrane as BSEP
- Transports: glucuronide conjugates (bilirubin-diglucuronide), sulfate conjugates, glutathione conjugates, methotrexate, cisplatin
- MRP2 inhibition → reduced biliary bilirubin excretion → conjugated hyperbilirubinemia (cholestatic jaundice)
- Often co-inhibited with BSEP by the same drugs — combined BSEP + MRP2 inhibition produces most severe cholestatic DILI
- EMA recommends MRP2 testing when signs of cholestasis or conjugated hyperbilirubinemia appear in preclinical/clinical data
- In vitro: inside-out membrane vesicle assay with HEK293-MRP2 vesicles and glutathione-methylfluorescein probe
Further Reading
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