ABCMdb

PMID: 12406647

Suzuki H, Sugiyama Y
Single nucleotide polymorphisms in multidrug resistance associated protein 2 (MRP2/ABCC2): its impact on drug disposition.
Adv Drug Deliv Rev. 2002 Nov 18;54(10):1311-31., [PubMed]

Sentences

No. Mutations Sentence Comment

32 ABCC1 p.Ala893Ser Moreover, Ala893Ser rabbit and human MRP2 [21,38,40,42-61], as sum- mutation in MDR1 gene results in the reduced oral marized in Refs. [7,23,25,26]. Login to comment 109 ABCC2 p.Arg1150His ABCC2 p.Ile1173Phe mutation, and deletion mutation have all been re- Moreover, I1173F and R1150H have been found ported. Login to comment 114 ABCC2 p.Arg1150His In addition, Western blot and immunohistochemical analysis indicated that, Asp1208Asn lost their ability to transport these although R1150H was mature and targeted to the conjugates (Fig. 2) [109]. Login to comment 115 ABCC2 p.Ile1173Arg Moreover, it was sug- plasma membrane, the expression of I1173R was gested that Arg586Lys/Ile and Arg1096Lys/Leu/ low and located in the ER [107]. Login to comment 116 ABCC2 p.Arg1150His The mechanism for Met transport monovalent bile salts, which are not the impaired function of R1150H remains to be transported by wt MRP2 (Fig. 2) [110]. Login to comment 120 ABCC2 p.Arg1257Ala ABCC2 p.Lys483Ala ABCB1 p.Arg210Ala It affecting MRP2 function was found that Lys24Ala (TM6), Lys483Ala (TM9), Arg210Ala (TM16) and Arg1257Ala (TM17) exhibit Several lines of investigation have been followed reduced transport activity for glutathione-conjugates to investigate the amino acid residues in MRP2 (Fig. 2) [111]. Login to comment 124 ABCC2 p.Trp1254Ala ABCC2 p.Trp1254Cys membrane domains conserved in organic anion Non-conservatively substituted Trp1254Ala and transporting MRP 1, 2 and 3, and examined their Trp1254Cys lost the ability to transport these three function by determining the transport of glucuronide types of substrates (Fig. 2) [112]. Login to comment 125 ABCC2 p.Trp1254Phe Conservatively and glutathione conjugates into the isolated mem- substituted Trp1254Phe transports E 17bG, but not2 brane vesicles from Sf9 cells expressing mutant rat LTC or methotrexate, whereas highly conservative-4 MRP2 [109]. Login to comment 126 ABCC2 p.Trp1254Tyr It was found that Lys325Met and ly substituted Trp1254Tyr transports E 17bG and2 Arg586Leu resulted in a marked reduction in the LTC , but not methotrexate (Fig. 2) [112].4 transport of glutathione-conjugates, whereas the In addition to the previously described mutation transport activity for glucuronide conjugates was found in a DJS patient, the carboxy-terminal se- retained (Fig. 2) [109]. Login to comment 134 ABCB1 p.Gly1249Ala G1249A is to the PDZ-interacting domain characterized by the associated with amino acid alterations from Val to Ile carboxy-terminal amino acid sequence Ser/Thr-Xat 417, whereas C3972T is the 'silent` mutation at hydrophobic residue, where X represents any amino 1324 (Ile1324Ile) (Fig. 3) [118]. Login to comment 137 ABCC2 p.Arg768Trp ABCC2 p.Ser789Phe Arg768Trp), C2366T (exon 18, Ser789Phe) and Although Harris et al. Login to comment 138 ABCC2 p.Ala1450Thr [116] suggested that this G4348A (exon 31, Ala1450Thr) (Fig. 3) [118]. Login to comment 145 ABCB1 p.Gly1249Ala The frequently observed SNPs in Japanese amino acid sequence in this region may be involved subjects (C-24T, G1249A and C3972T) were also in the apical targeting, stabilization, and/or in main- found very often in the established cell lines. Login to comment 152 ABCB1 p.Gly1249Ala Therefore, it is possible that some SNP them, C-24T (promoter), G1249A (exon 10) and mutations observed at a lower frequency are associ- Fig. 3. Login to comment 159 ABCC2 p.Ala1450Thr It is possible that the induction by G4348A/Ala1450Thr mutation is located in the food and/or drugs may also be at least partly Walker C motif within the carboxy terminal NBD involved in determining the expression level of region, which may affect MRP2 function. Login to comment 313 ABCC1 p.Arg1066* Raymakers, M. Muller, E. van Den Berg, E.G. de Vries, [105] T. Kagawa, M. Sato, K. Hosoi, J. Uchiyama, Y. Nishizaki, Deletion of the multidrug resistance protein MRP1 gene in N. Watanabe, Y. Inagaki, M. Kimura, S. Matsuzaki, Ab- acute myeloid leukemia: the impact on MRP activity, Blood sence of R1066X mutation in six Japanese patients with 95 (2000) 3514-3519. Login to comment