The Dubin-Johnson syndrome is characterized by an patocytes into the bile. 3,4 This defect results in predomiinherited defect in the secretion of amphiphilic anionic nantly conjugated hyperbilirubinemia and a characterconjugates from hepatocytes into the bile. We have reistic secondary rise of intravenously administered cently identified the membrane protein mediating the sulfobromophthalein in blood plasma following its conadenosine triphosphate (ATP)-dependent transport of jugation with glutathione in hepatocytes and transport glutathione and glucuronate conjugates as a multidrugof the conjugate from hepatocytes to the blood. [3][4][5][6][7][8][9] Macresistance protein (MRP) and localized it to the canalicuroscopic examination of the liver from patients with lar as well as to the lateral hepatocyte plasma mem-Dubin-Johnson syndrome shows it to be intensely pigbrane. In the present study we show the selective mented with an appearance described as grossly black 2 absence of the canalicular isoform of MRP (cMRP) from the hepatocytes in a patient with Dubin-Johnson synor dark blue. 10 Several most useful animal models of drome by double-label immunofluorescence and confothis defect in human hepatobiliary transport have been cal laser scanning microscopy using antibodies didescribed and extensively studied. 3,[11][12][13][14][15][16] In the transrected against MRP and dipeptidyl-peptidase IV port-deficient GY/TR 0 mutant Wistar rat 11 a selective (DPPIV). Another isoform of MRP was detected, howcanalicular defect in the ATP-dependent transport of ever, in the lateral hepatocyte membrane of the paglutathione S-conjugates and other nonbile salt organic tient. Moreover, MRP was present on immunoblots of anions has been shown. [16][17][18] Our recent work has shown erythrocyte membranes from Dubin-Johnson synthat this defect in GY/TR 0 mutants results from the drome and normal humans. These findings are analogous to our recent observations on the localization of selective absence of the canalicular isoform of the ATPthe rat homolog of MRP and its canalicular isoform, dependent conjugate export pump, which is encoded cMrp, in normal and transport-deficient GY/TR 0 Wistar by a rat homolog of MRP gene, from the hepatocyte rat liver. The elucidation of the selective absence of an canalicular membrane. 16 isoform of MRP and from the canalicular membrane The multidrug resistance protein (MRP) has been domain in conjunction with the defined substrate specidentified in multidrug resistant tumor cells as a memificity of the MRP and cMRP gene-encoded conjugate brane glycoprotein with a molecular mass of 170 to 195 export pumps contributes to the molecular definition kd. 19-22 Sequence analysis has indicated that the MRP of the transport defect in Dubin-Johnson syndrome. (HEPATOLOGY 1996;23:1061-1066.)
gene encodes an ATP-binding integral membrane transport protein. 19 The function of MRP as an ATP-The Dubin-Johnson syndrome, originally described dependent export pump for conjugates of lipophilic in 1954, 1,2 is an autosomal recessively transmitted compounds with anionic residues such as glutathione disorder characterized by a defect in the transfer of and glucuronate has been elucidated in human tumor endogenous and exogenous anionic conjugates from hecells overexpressing MRP and in cells transfected with an MRP expression vector. [23][24][25] The expression of MRP Abbreviations: ATP, adenosine triphosphate; MRP, multidrug-resistance isoforms in human liver and their localization to the protein; DPPIV, dipeptidyl-peptidase IV. canalicular as well as to the lateral hepatocyte plasma From the 1 Division of Cell Biology, Deutsches Krebsforschungszentrum, membrane have been recognized recently. 16 In the pres-