PMID- 10421658
OWN - NLM
STAT- MEDLINE
DCOM- 19990812
LR  - 20131121
IS  - 0270-9139 (Print)
IS  - 0270-9139 (Linking)
VI  - 30
IP  - 2
DP  - 1999 Aug
TI  - Transport of monoglucuronosyl and bisglucuronosyl bilirubin by recombinant human 
      and rat multidrug resistance protein 2.
PG  - 485-90
AB  - 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, (3)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 micromol/L each) by human MRP2 were
      183 and 104 pmol x mg protein(-1) x min(-1), respectively. K(m) values were 0.7
      and 0.9 micromol/L for human MRP2, and 0.8 and 0.5 micromol/L for rat MRP2, with 
      MGB and BGB as substrates, respectively. Leukotriene C(4) and 17beta-glucuronosyl
      estradiol, which are both known high-affinity substrates for human MRP2,
      inhibited [(3)H]MGB transport with IC(50) values of 2.3 and 30 micromol/L,
      respectively. Cyclosporin A competitively inhibited human and rat MRP2-mediated
      transport of [(3)H]MGB, with K(i) values of 21 and 10 micromol/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.
FAU - Kamisako, T
AU  - Kamisako T
AD  - Division of Tumor Biochemistry, Deutsches Krebsforschungszentrum, Heidelberg,
      Germany.
FAU - Leier, I
AU  - Leier I
FAU - Cui, Y
AU  - Cui Y
FAU - Konig, J
AU  - Konig J
FAU - Buchholz, U
AU  - Buchholz U
FAU - Hummel-Eisenbeiss, J
AU  - Hummel-Eisenbeiss J
FAU - Keppler, D
AU  - Keppler D
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Glucuronates)
RN  - 0 (MRP2 protein, S cerevisiae)
RN  - 0 (Mitochondrial Proteins)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Ribosomal Proteins)
RN  - 0 (Saccharomyces cerevisiae Proteins)
RN  - 2CU6TT9V48 (Leukotriene C4)
RN  - 83HN0GTJ6D (Cyclosporine)
RN  - RFM9X3LJ49 (Bilirubin)
SB  - IM
MH  - Animals
MH  - Bilirubin/*metabolism
MH  - Biological Transport
MH  - Cyclosporine/pharmacology
MH  - Glucuronates/*metabolism
MH  - HeLa Cells
MH  - Humans
MH  - Immunoblotting
MH  - Leukotriene C4/metabolism
MH  - *Mitochondrial Proteins
MH  - Rats
MH  - Recombinant Proteins/pharmacology
MH  - Ribosomal Proteins/*pharmacology
MH  - *Saccharomyces cerevisiae Proteins
MH  - Substrate Specificity
EDAT- 1999/07/27 00:00
MHDA- 1999/07/27 00:01
CRDT- 1999/07/27 00:00
PHST- 1999/07/27 00:00 [pubmed]
PHST- 1999/07/27 00:01 [medline]
PHST- 1999/07/27 00:00 [entrez]
AID - S0270913999003705 [pii]
AID - 10.1002/hep.510300220 [doi]
PST - ppublish
SO  - Hepatology. 1999 Aug;30(2):485-90. doi: 10.1002/hep.510300220.