{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T23:15:45Z","timestamp":1770506145523,"version":"3.49.0"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":5875,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"name":"Deutsche Forschungsgemeinschaft through","award":["SFB352\/B3"],"award-info":[{"award-number":["SFB352\/B3"]}]},{"name":"Deutsche Forschungsgemeinschaft through","award":["SFB 601\/A2"],"award-info":[{"award-number":["SFB 601\/A2"]}]},{"name":"Heidelberg, and the Alexander von Humboldt-Stiftung, Bonn, Germany"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[1999,8]]},"abstract":"<jats:sec><jats:title\/><jats:p>The secretion of bilirubin conjugates from hepatocytes into bile represents a decisive step in the prevention of hyperbilirubinemia. The bilirubin conjugates, monoglucuronosyl bilirubin (MGB) and bisglucuronosyl bilirubin (BGB), were previously suggested to be endogenous substrates for the apical multidrug resistance protein (MRP2), a member of the adenosine triphosphate (ATP)-binding cassette family of transporters (symbol ABCC2), also termed canalicular multispecific organic anion transporter. We have characterized this ATP-dependent transport using membrane vesicles from human embryonic kidney (HEK) cells expressing recombinant rat as well as human MRP2. MGB and BGB,<jats:sup>3<\/jats:sup>H-labeled in the glucuronosyl moiety, were synthesized enzymatically with recombinant UDP-glucuronosyltransferase 1A1, and stabilized with ascorbate. Rates for ATP-dependent transport of MGB and BGB (0.5 \u03bcmol\/L each) by human MRP2 were 183 and 104 pmol \u00d7 mg protein<jats:sup>\u22121<\/jats:sup>\u00d7 min<jats:sup>\u22121<\/jats:sup>, respectively.<jats:italic toggle=\"yes\">K<\/jats:italic><jats:sub>m<\/jats:sub>values were 0.7 and 0.9 \u03bcmol\/L for human MRP2, and 0.8 and 0.5 \u03bcmol\/L for rat MRP2, with MGB and BGB as substrates, respectively. Leukotriene C<jats:sub>4<\/jats:sub>and 17\u03b2-glucuronosyl estradiol, which are both known high-affinity substrates for human MRP2, inhibited [<jats:sup>3<\/jats:sup>H]MGB transport with IC<jats:sub>50<\/jats:sub>values of 2.3 and 30 \u03bcmol\/L, respectively. Cyclosporin A competitively inhibited human and rat MRP2-mediated transport of [<jats:sup>3<\/jats:sup>H]MGB, with<jats:italic toggle=\"yes\">K<\/jats:italic><jats:sub>i<\/jats:sub>values of 21 and 10 \u03bcmol\/L, respectively. Our results provide direct evidence that recombinant MRP2, cloned from rat as well as human liver, mediates the primary-active ATP-dependent transport of the bilirubin conjugates MGB and BGB.<\/jats:p><\/jats:sec>","DOI":"10.1002\/hep.510300220","type":"journal-article","created":{"date-parts":[[2004,7,28]],"date-time":"2004-07-28T07:26:28Z","timestamp":1090999588000},"page":"485-490","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":155,"title":["Transport of monoglucuronosyl and bisglucuronosyl bilirubin by recombinant human and rat multidrug resistance protein 2"],"prefix":"10.1097","volume":"30","author":[{"given":"Toshinori","family":"Kamisako","sequence":"first","affiliation":[]},{"given":"Inka","family":"Leier","sequence":"additional","affiliation":[]},{"given":"Yunhai","family":"Cui","sequence":"additional","affiliation":[]},{"given":"J\u00f6rg","family":"K\u00f6nig","sequence":"additional","affiliation":[]},{"given":"Ulrike","family":"Buchholz","sequence":"additional","affiliation":[]},{"given":"Johanna","family":"Hummel-Eisenbeiss","sequence":"additional","affiliation":[]},{"given":"Dietrich","family":"Keppler","sequence":"additional","affiliation":[]}],"member":"276","reference":[{"key":"10.1002\/hep.510300220-BIB1|cit1","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1042\/bj0650774","article-title":"Excretion of bilirubin as a diglucuronide giving the direct van den Bergh reaction","volume":"65","author":"Billing","year":"1957","journal-title":"Biochem J"},{"key":"10.1002\/hep.510300220-BIB2|cit2","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1172\/JCI103702","article-title":"Congenital jaundice in rats, due to a defect in glucuronide formation","volume":"37","author":"Schmid","year":"1958","journal-title":"J Clin Invest"},{"key":"10.1002\/hep.510300220-BIB3|cit3","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1152\/ajplegacy.1961.200.5.1091","article-title":"Biliary excretion of injected conjugated and unconjugated bilirubin by normal and Gunn rats","volume":"200","author":"Arias","year":"1961","journal-title":"Am J Physiol"},{"key":"10.1002\/hep.510300220-BIB4|cit4","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1002\/hep.1840050408","article-title":"Hereditary chronic conjugate hyperbilirubinemia in mutant rats caused by defective hepatic anion transport","volume":"5","author":"Jansen","year":"1985","journal-title":"Hepatology"},{"key":"10.1002\/hep.510300220-BIB5|cit5","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1016\/0024-3205(91)90301-Q","article-title":"Organic anion transport study in mutant rats with autosomal recessive conjugated hyperbilirubinemia","volume":"49","author":"Kurisu","year":"1991","journal-title":"Life Sci"},{"key":"10.1002\/hep.510300220-BIB6|cit6","doi-asserted-by":"crossref","first-page":"3557","DOI":"10.1073\/pnas.87.9.3557","article-title":"Defective ATP-dependent bile canalicular transport of organic anions in mutant (TR\u2212) rats with conjugated hyperbilirubinemia","volume":"87","author":"Kitamura","year":"1990","journal-title":"Proc Natl Acad Sci U S A"},{"key":"10.1002\/hep.510300220-BIB7|cit7","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1002\/hep.1840070204","article-title":"Hereditary defect of hepatobiliary cysteinyl leukotriene elimination in mutant rats with defective hepatic anion excretion","volume":"7","author":"Huber","year":"1987","journal-title":"Hepatology"},{"key":"10.1002\/hep.510300220-BIB8|cit8","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1172\/JCI113493","article-title":"Separate transport systems for biliary secretion of sulfated and unsulfated bile acids in the rat","volume":"81","author":"Kuipers","year":"1988","journal-title":"J Clin Invest"},{"key":"10.1002\/hep.510300220-BIB9|cit9","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/0304-4157(95)00006-D","article-title":"Hepatobiliary secretion of organic compounds; molecular mechanisms of membrane transport","volume":"1241","author":"Oude Elferink","year":"1995","journal-title":"Biochim Biophys Acta"},{"key":"10.1002\/hep.510300220-BIB10|cit10","doi-asserted-by":"crossref","first-page":"19279","DOI":"10.1016\/S0021-9258(17)30655-5","article-title":"ATP-dependent primary active transport of cysteinyl leukotrienes across liver canalicular membrane. 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