ABCMdb

PMID: 12130697

Gerk PM, Vore M
Regulation of expression of the multidrug resistance-associated protein 2 (MRP2) and its role in drug disposition.
J Pharmacol Exp Ther. 2002 Aug;302(2):407-15., [PubMed]

Sentences

No. Mutations Sentence Comment

38 ABCC2 p.Arg1150His Unlike other mutations, R1150H mutants of the MRP2 protein mature and are properly localized, but transport activity is impaired (Mor-Cohen et al., 2001). Login to comment 49 ABCC2 p.Arg1257Ala ABCC2 p.Arg1210Ala ABCC2 p.Lys324Ala ABCC2 p.Lys483Ala Thirteen basic residues (His, Arg, Lys) in these regions were substituted with alanine; four mutants (K324A in TM6, K483A in TM9, R1210A in TM16 and R1257A in TM17) were all delivered appropriately to the cell surface when expressed in COS-7 cells yet showed decreased efflux of the substrate (Ryu et al., 2000). Login to comment 51 ABCC7 p.Glu217Gly Site-directed mutagenesis of Lys to Met (K325M) and Arg to Leu (R586L) of rat Mrp2 markedly reduced transport of DNP-SG and leukotriene C4, without affecting transport capacity of model glucuronide and sulfate conjugates yet increased the affinity for transport of E217G (Ito et al., 2001c). Login to comment 53 ABCC2 p.Arg768Trp ABCC2 p.Arg768Trp ABCC2 p.Arg768Trp ABCC2 p.Arg768Trp ABCC2 p.Arg1150His ABCC2 p.Arg1150His ABCC2 p.Ser789Phe ABCC2 p.Ala1450Thr ABCC2 p.Ile1173Phe ABCC2 p.Ile1173Phe Site-directed mutagenesis studies substi- TABLE 1 Mutations in human MRP2 Mutation Location Translation Domain Phenotype Reference -24(C-T) Promoter 5Ј-UTR Not reported (Ito et al., 2001e) 1249(G-A)/wt Exon 10 V4171 MSD2 Not reported (Ito et al., 2001e) 1815ϩ2(T-A)/1815ϩ2(T-A) Exon 13 147-bp deletion MSD2 DJS (Wada et al., 1998; Toh et al., 1999) 2002del67/2002del67 Exon 16 Premature termination codon NBD1 DJS (Konig et al., 1999a) 2302(C-T)/2302(C-T) Exon 18 R768W/R768W NBD1 DJS (Wada et al., 1998; Toh et al., 1999; Ito et al., 2001e) 2302(C-T)/2439ϩ2(T-C) Exon 18 R768W/168-bp deletion NBD1 DJS (Toh et al., 1999) 2302(C-T)/wt Exon 18 R768W/wt NBD1 Increased UCP1 (Toh et al., 1999) 2366(C-T)/wt Exon 18 S789F/wt NBD1 Not reported (Ito et al., 2001e) 2439ϩ2(T-C)/2439ϩ2(T-C) Exon 18 168-bp deletion/168-bp deletion NBD1 DJS (Wada et al., 1998; Toh et al., 1999) 2439ϩ2(T-C)/4145(A-G) Exon 18/29 168-bp deletion/Q1328R NBD1/2 DJS (Toh et al., 1999) 2439ϩ2(T-C)/wt Exon 18 168-bp deletion/wt NBD1 Increased UCP1 (Toh et al., 1999) 3196(C-T)/3196(C-T) Exon 23 Premature termination codon MSD3 DJS (Paulusma et al., 1997; Tsujii et al., 1999) 3449(G-A)/3449(G-A) Exon 25 R1150H/R1150H MSD3 DJS (Mor-Cohen et al., 2001) 3517(A-T)/3517(A-T) Exon 25 I1173F/I1173F MSD3 DJS (Mor-Cohen et al., 2001) 3972(C-T)/wt Exon 28 I1324I/wt near NBD2 None (Ito et al., 2001e) 4175del6 Exon 30 Loss of R1392 and M1393 NBD2 DJS (Tsujii et al., 1999) 4348(G-A)/wt Exon 31 A1450T/wt NBD2 Not reported (Ito et al., 2001e) UTR, untranslated region; wt, wild type; bp, base pair; UCP1, urinary coproporphyrin fraction 1. tuting the cationic amino acid Arg586 and Arg1096 in rat Mrp2 with neutral amino acids (R586L, R586I, R1096L, and R1096M) or a cationic amino acid (R1096K) led to acquisition of taurocholate transport and retention of glucuronide and glutathione conjugate transport by Mrp2 (Ito et al., 2001d). Login to comment 55 ABCC7 p.Glu217Gly In other recent studies, a highly conserved tryptophan residue, Trp1246 , in the last transmembrane segment (TM17) of MSD3 of MRP1 has been shown to be essential for transport of E217G (Ito et al., 2001b). Login to comment 56 ABCC7 p.Glu217Gly Mutation of the analogous Trp1254 of MRP2 showed this amino acid to be essential for MRP2 transport of methotrexate; nonconservative substitutions (Ala, Cys) eliminated E217G transport, whereas conservative substitutions (Tyr, Phe) were without effect (Ito et al., 2001a). Login to comment 57 ABCC2 p.Trp1254Tyr Only the most conservative substitution (W1254Y) retained leukotriene C4 transport activity. Login to comment 87 ABCC7 p.Glu217Gly Finally, E217G causes a rapid inhibition of bile flow and retrieval of Mrp2 into intracellular sites; bile flow recovers spontaneously and is followed by the exocytic insertion of Mrp2 into the canalicular membrane (Mottino et al., 2002). Login to comment 129 ABCC7 p.Glu217Gly The transport efficiency (Vmax/Km) of substrates for rat and human MRP2 have been ranked as follows: leukotriene C4 Ͼ leukotriene D4 Ͼ 2,4DNP-SG Ͼ monoglucuronosyl bilirubin Ͼ E217G Ͼ taurolithocholate sulfate Ͼ oxidized glutathione (Keppler et al., 1997). Login to comment 157 ABCC7 p.Glu217Gly When the cells were grown to confluent monolayers, transcellular transport of bromosulfophthalein, leukotriene C4, E217G, dehydroepiandrosterone sulfate, Fluo-3, and rifampin was higher in double-transfected (OATP8/MRP2) cells than in single-transfected (MRP2 only) cells (Cui et al., 2001). Login to comment 158 ABCC7 p.Glu217Gly Similarly, Sasaki et al. (2002) coexpressed OATP2 (SLC21A6) and MRP2 in MDCKII cells and demonstrated vectorial transport of E217G, leukotriene C4, and taurolithocholate sulfate but not dehydroepiandrosterone sulfate or estrone-3-sulfate. Login to comment 164 ABCC7 p.Glu217Gly Similarly, E217G inhibited Bsep in Bsep/ Mrp2 coexpressing Sf9 membrane vesicles but not in Bsep- alone expressing Sf9 membrane vesicles (Stieger et al., 2000). Login to comment 172 ABCC7 p.Glu217Gly ABCC7 p.Glu217Gly Similarly, although E217G is a substrate for MDR1 expressed in Sf9 insect cells, there is no measurable E217G-stimulated ATPase activity (Huang et al., 1998). Login to comment 186 ABCC2 p.Arg1150His Since MRP2 seems to act as a protective barrier in the TABLE 2 Factors altering MRP2/Mrp2 mRNA or protein expression and function in vitro or in vivo, as discussed in the text Regulation of expression Renal failure Pregnancy and lactation Cholestasis MRP2 mutations Sepsis (lipopolysaccharide) Hypo-or hyperosmolarity Phalloidin Bile duct ligation Acute-phase response Rifampin FXR, CAR, and PXR ligands Dibutyryl cAMP Inhibition or stimulation of activity ATP depletion Estrogen glucuronides Cholestasis MRP2 mutation: R1150H Cancer chemotherapeutics: irinotecan, methotrexate, and vinblastine Uricosurics: sulfinpyrazone, probenecid, and benzbromarone brain, intestine, and placenta, MRP2 alterations may also affect the absorption and distribution of these compounds, thus affecting therapeutics or toxicology. Login to comment