![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 59, Issue 5, 1077-1085, May 2001
Graduate School of Pharmaceutical Sciences, The University of
Tokyo, Tokyo, Japan
Multidrug resistance-associated protein 2 (MRP2) transports glutathione
conjugates, glucuronide conjugates, and sulfated conjugates of bile
acids. In the present study, we examined the role of charged amino acids in the transmembrane domains of rat Mrp2, conserved among
MRP families, using the isolated membrane vesicles from Sf9 cells
infected with the recombinant baculoviruses. By normalizing the
transport activity for compounds by that for estradiol
17
-D-glucuronide (E217G), it was
indicated that the site-directed mutagenesis from Lys to Met at 325 (K325M) and from Arg to Leu at 586 (R586L) results in a marked
reduction in the transport for glutathione conjugates
[2,4-dinitrophenyl-S-glutathione (DNP-SG) and
leukotriene (LT) C4] without affecting that for
6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridymethyl) benzothiazole glucuronide and taurolithocholate sulfate. In
contrast to the reduced affinity for DNP-SG, the affinity for
E217G was increased severalfold in these mutant Mrp2s,
suggesting the amino acids at 325 and 586 play an important role in
distinguishing between glutathione and glucuronide conjugates. The
comparable affinity for LTD4, LTE4, and
LTF4 in these mutant Mrp2s with that in wild-type Mrp2
indicates that recognition of LTC4 metabolites by Mrp2 is
different from that of LTC4. The transport activity for
glutathione conjugate was retained on R586K, whereas no such complementary cationic amino acid effect was observed in K325R. In
addition, R1206M and E1208Q exhibited the loss of transport activity
for the tested compounds. The results of the present study demonstrate
that the charged amino acids in the transmembrane domain of rat Mrp2
may play an important role in the recognition and/or transport of its substrates.
This article has been cited by other articles:
|
|
 |
|
  N. Yoshida, T. Takada, Y. Yamamura, I. Adachi, H. Suzuki, and J. Kawakami Inhibitory Effects of Terpenoids on Multidrug Resistance-Associated Protein 2- and Breast Cancer Resistance Protein-Mediated Transport Drug Metab. Dispos., July 1, 2008; 36(7): 1206 - 1211. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Kato, S. Takahara, S. Kato, Y. Kubo, Y. Sai, I. Tamai, H. Yabuuchi, and A. Tsuji Involvement of Multidrug Resistance-Associated Protein 2 (Abcc2) in Molecular Weight-Dependent Biliary Excretion of {beta}-Lactam Antibiotics Drug Metab. Dispos., June 1, 2008; 36(6): 1088 - 1096. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Heredi-Szabo, E. Kis, E. Molnar, A. Gyorfi, and P. Krajcsi Characterization of 5(6)-Carboxy-2,'7'-Dichlorofluorescein Transport by MRP2 and Utilization of this Substrate as a Fluorescent Surrogate for LTC4 J Biomol Screen, April 1, 2008; 13(4): 295 - 301. [Abstract] [PDF]
|
|
|
|
|
|
M. Ninomiya, K. Ito, R. Hiramatsu, and T. Horie Functional Analysis of Mouse and Monkey Multidrug Resistance-Associated Protein 2 (Mrp2) Drug Metab. Dispos., December 1, 2006; 34(12): 2056 - 2063. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. G. Deeley, C. Westlake, and S. P. C. Cole Transmembrane Transport of Endo- and Xenobiotics by Mammalian ATP-Binding Cassette Multidrug Resistance Proteins. Physiol Rev, July 1, 2006; 86(3): 849 - 899. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ninomiya, K. Ito, and T. Horie FUNCTIONAL ANALYSIS OF DOG MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN 2 (MRP2) IN COMPARISON WITH RAT MRP2 Drug Metab. Dispos., February 1, 2005; 33(2): 225 - 232. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Gerk, W. Li, and M. Vore ESTRADIOL 3-GLUCURONIDE IS TRANSPORTED BY THE MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN 2 BUT DOES NOT ACTIVATE THE ALLOSTERIC SITE BOUND BY ESTRADIOL 17-GLUCURONIDE Drug Metab. Dispos., October 1, 2004; 32(10): 1139 - 1145. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Ito, T. Koresawa, K. Nakano, and T. Horie Mrp2 is involved in benzylpenicillin-induced choleresis Am J Physiol Gastrointest Liver Physiol, July 1, 2004; 287(1): G42 - G49. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Haimeur, G. Conseil, R. G. Deeley, and S. P.C. Cole Mutations of Charged Amino Acids in or near the Transmembrane Helices of the Second Membrane Spanning Domain Differentially Affect the Substrate Specificity and Transport Activity of the Multidrug Resistance Protein MRP1 (ABCC1) Mol. Pharmacol., June 1, 2004; 65(6): 1375 - 1385. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Li, K. Ito, and T. Horie Transport of fluorescein methotrexate by multidrug resistance-associated protein 3 in IEC-6 cells Am J Physiol Gastrointest Liver Physiol, August 8, 2003; 285(3): G602 - G610. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Godinot, P. W. Iversen, L. Tabas, X. Xia, D. C. Williams, A. H. Dantzig, and W. L. Perry III Cloning and Functional Characterization of the Multidrug Resistance-associated Protein (MRP1/ABCC1) from the Cynomolgus Monkey Mol. Cancer Ther., March 1, 2003; 2(3): 307 - 316. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Oleschuk, R. G. Deeley, and S. P. C. Cole Substitution of Trp1242 of TM17 alters substrate specificity of human multidrug resistance protein 3 Am J Physiol Gastrointest Liver Physiol, February 1, 2003; 284(2): G280 - G289. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-Y. Cai, C. J. Soroka, N. Ballatori, and J. L. Boyer Molecular characterization of a multidrug resistance-associated protein, Mrp2, from the little skate Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2003; 284(1): R125 - R130. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Haimeur, R. G. Deeley, and S. P. C. Cole Charged Amino Acids in the Sixth Transmembrane Helix of Multidrug Resistance Protein 1 (MRP1/ABCC1) Are Critical Determinants of Transport Activity J. Biol. Chem., October 25, 2002; 277(44): 41326 - 41333. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Xiong, H. Suzuki, Y. Sugiyama, P. J. Meier, G. M. Pollack, and K. L. R. Brouwer Mechanisms of Impaired Biliary Excretion of Acetaminophen Glucuronide after Acute Phenobarbital Treatment or Phenobarbital Pretreatment Drug Metab. Dispos., September 1, 2002; 30(9): 962 - 969. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. M. Gerk and M. Vore Regulation of Expression of the Multidrug Resistance-Associated Protein 2 (MRP2) and Its Role in Drug Disposition J. Pharmacol. Exp. Ther., August 1, 2002; 302(2): 407 - 415. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ito, H. Suzuki, and Y. Sugiyama Single amino acid substitution of rat MRP2 results in acquired transport activity for taurocholate Am J Physiol Gastrointest Liver Physiol, October 1, 2001; 281(4): G1034 - G1043. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D.-W. Zhang, S. P. C. Cole, and R. G. Deeley Identification of a Nonconserved Amino Acid Residue in Multidrug Resistance Protein 1 Important for Determining Substrate Specificity. EVIDENCE FOR FUNCTIONAL INTERACTION BETWEEN TRANSMEMBRANE HELICES 14 AND 17 J. Biol. Chem., September 7, 2001; 276(37): 34966 - 34974. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-i. Ito, C. J. Oleschuk, C. Westlake, M. Z. Vasa, R. G. Deeley, and S. P. C. Cole Mutation of Trp1254 in the Multispecific Organic Anion Transporter, Multidrug Resistance Protein 2 (MRP2) (ABCC2), Alters Substrate Specificity and Results in Loss of Methotrexate Transport Activity J. Biol. Chem., October 5, 2001; 276(41): 38108 - 38114. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
