{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T18:53:48Z","timestamp":1773428028232,"version":"3.50.1"},"reference-count":41,"publisher":"American Physiological Society","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Gastrointestinal and Liver Physiology"],"published-print":{"date-parts":[[2003,1,1]]},"abstract":"<jats:p>Absence of a functional multidrug resistance protein 2 (MRP2; symbol ABCC2) from the hepatocyte canalicular membrane is the molecular basis of Dubin- Johnson syndrome, an inherited disorder associated with conjugated hyperbilirubinemia in humans. In this work, we analyzed a relatively frequent Dubin-Johnson syndrome mutation that leads to an exchange of two hydrophobic amino acids, isoleucine 1173 to phenylalanine (MRP2I1173F), in a predicted extracellular loop of MRP2. HEK-293 cells stably transfected with MRP2I1173F cDNA synthesized a mutant protein that was mainly core-glycosylated, predominantly retained in the endoplasmic reticulum, and degraded by proteasomes. MRP2I1173F did not mediate ATP-dependent transport of leukotriene C<jats:sub>4<\/jats:sub>(LTC<jats:sub>4<\/jats:sub>) into vesicles from plasma membrane and endoplasmic reticulum preparations while normal MRP2 was functionally active. Human HepG2 cells were used to study localization of MRP2I1173F in a polarized cell system. Quantitative analysis showed that GFP-tagged MRP2I1173F was localized to the apical membrane in only 5% of transfected, polarized HepG2 cells compared with 80% for normal MRP2-GFP. Impaired protein maturation followed by proteasomal degradation of inactive MRP2I1173F explain the deficient hepatobiliary elimination observed in this group of Dubin-Johnson syndrome patients.<\/jats:p>","DOI":"10.1152\/ajpgi.00362.2002","type":"journal-article","created":{"date-parts":[[2015,3,3]],"date-time":"2015-03-03T22:36:11Z","timestamp":1425422171000},"page":"G165-G174","source":"Crossref","is-referenced-by-count":106,"title":["A common Dubin-Johnson syndrome mutation impairs protein maturation and transport activity of MRP2 (ABCC2)"],"prefix":"10.1152","volume":"284","author":[{"given":"Verena","family":"Keitel","sequence":"first","affiliation":[{"name":"Division of Tumor Biochemistry and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne T.","family":"Nies","sequence":"additional","affiliation":[{"name":"Division of Tumor Biochemistry 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