ABCMdb

ABCB1 p.Phe103Leu

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PMID: 15882131 [PubMed] Lepper ER et al: "Mechanisms of resistance to anticancer drugs: the role of the polymorphic ABC transporters ABCB1 and ABCG2."

No. Sentence Comment

90 A detailed analysis of the potential functional consequences of different ABCB1 variants has not yet been performed, except for the five most common non-synonymous coding SNPs (i.e., Asn21Asp, Phe103Leu, Ser400Asn, Ala893Ser/Thr, and Ala998Thr) as assessed by a vaccinia virus-based transient expression system [74]. Login to comment
106 Nonetheless, the association of the C3435T polymorphism with Table 2. Summary of common genetic variants in the ABCB1 gene cDNA position* Region‡ Wild-type allele Variant allele Amino acid Change§ -274 Intron -1 G A -223 Intron -1 C T -146 Intron -1 T C -60 Intron -1 A T -41 Intron -1 A G Non-coding -241 Exon 1 G A Non-coding -145 Exon 1 C G Non-coding -129 Exon 1 T C Non-coding -43 Exon 1 A G Non-coding +140 Intron 1 C A +237 Intron 1 G A -4 Exon 2 C T Non-coding -1 Exon 2 G A Non-coding 61 Exon 2 A G 21 Asn to Asp -8 Intron 3 C G 266 Exon 4 T C 89 Met to Thr 307 Exon 5 T C 103 Phe to Leu -25 Intron 4 G T +139 Intron 6 C T +145 Intron 6 C T 548 Exon 7 A G 183 Asn to Ser 729 Exon 8 A G 243 Syn 781 Exon 8 A G 261 Ile to Val -44 Intron 9 A G -41 Intron 10 T G 1199 Exon 11 G A 400 Ser to Asn -4 Intron 11 G A 1236¶ Exon 12 C T 412 Syn 1308 Exon 12 A G 436 Syn +17 Intron 12 G A +44 Intron 12 C T 1474 Exon 13 C T 492 Arg to Cys +24 Intron 13 C T 1617 Exon 14 C T 539 Syn +38 Intron 14 A G +38 Intron 15 G A 1985 Exon 16 T G 662 Leu to Arg 2005 Exon 16 C T 669 Arg to Cys -27 Intron 17 A G +8 Intron 20 C G *cDNA numbers are relative to the ATG site and based on the cDNA sequence from GenBank accession number M14758 with an A as the reference at position 43. Login to comment

PMID: 16259577 [PubMed] Sakurai A et al: "Genetic polymorphisms of ATP-binding cassette transporters ABCB1 and ABCG2: therapeutic implications."

No. Sentence Comment

94 Kimchi-Sarfaty et al. [73] assessed the five most common coding SNPs (i.e., N21D, F103L, S400N, A893S and A999T) by using a vaccinia virus-based transient expression system. Login to comment
106 Position Allele Amino acid Allele frequency in Caucasian populations Allele frequency in Japanese populatins Allele frequency in African populations n % n % n % 61 A G 21 Asn 21 Asp 799 89.7 10.3 193 100 0 100 97.5 2.5 266 T C 89 Met 89 Thr 100 99.5 0.5 145 100 0 100 100 0 307 T C 103 Phe 103 Leu 546 99.9 0.1 48 100 0 ND ND ND 325 G A 108 Glu 108 Lys ND ND ND 37 95.9 4.1 ND ND ND 781 A G 261 Ile 261 Val 100 100 0 145 100 0 100 98.5 1.5 1199 G A 400 Ser 400 Asn 696 95.0 5.0 193 100 0 100 99 1 1985 T G 662 Leu 662 Arg 100 99.5 0.5 145 100 0 100 100 0 2005 C T 669 Arg 669 Cys 100 100 0 145 100 0 100 99 1 2485 A G 829 Ile 829 Val 185 99.2 0.8 ND ND ND ND ND ND 2547 A G 849 Ile 849 Met 100 99.5 0.5 145 100 0 100 100 0 2677 G T A 893 Ala 893 Ser 893 Thr 611 55.1 42.1 2.8 241 40.0 41.1 18.9 100 90 10 0.5 2956 A G 986 Met 986 Val ND ND ND 100 99.5 0.5 ND ND ND 3151 C G 1051 Pro 1051 Ala 100 100 0 145 100 0 100 99.5 0.5 3320 A C 1107 Gln 1107 Pro 461 99.8 0.2 ND ND ND ND ND ND 3322 T C 1108 Trp 1108 Arg 100 100 0 145 100 0 100 99.5 0.5 3421 T A 1141 Ser 1141 Thr 100 100 0 145 100 0 100 88.9 11.1 3751 G A 1251 Val 1251 Ile 100 100 0 145 99 1 100 100 0 3767 C A 1256 Thr 1256 Lys 100 99.5 0.5 145 100 0 100 100 0 Data from [31-38, 203]. Login to comment
129 N21D M89T N44S H2N F103L E108K N183S G185V I261V S400N R492C A599T L662R R669C V801M A893S/T I829V I849M M986V A999T G1063A P1051A Q1107P W1108R I1145M S1141T V1251I T1256K COOH ATP-binding site ATP-binding site EXTRACELLULAR INTRACELLULAR A80E Figure 2. Login to comment

PMID: 18855611 [PubMed] Zhou SF et al: "Clinical pharmacogenetics and potential application in personalized medicine."

No. Sentence Comment

487 Exon 2 contains a polymorphism that changes Asn21 to Asp, and the mutation at exon 5 changes Phe103 to Leu. Login to comment

PMID: 19200005 [PubMed] Porcelli L et al: "Intracellular trafficking of MDR transporters and relevance of SNPs."

No. Sentence Comment

229 [113], who showed that HeLa cells transfected with either the wild-type or the ABCB1 polymorphisms A61G (N21D), T307C (F103L), G1199A (S400N), G2677T (A893S) and G2995A (A998T) expressed the transporter at the cell surface. Login to comment

PMID: 11258197 [PubMed] Kerb R et al: "ABC drug transporters: hereditary polymorphisms and pharmacological impact in MDR1, MRP1 and MRP2."

No. Sentence Comment

97 SNP Region N Frequency of SNPs (%) Effect Heterozygous Homozygous Observed Estimated T-12C E1 85 11.8 0 0.4 Non-coding G-1A E2 188 11.2 0 0.4 TL initiation A61G E2 188 17.6 0.5 0.81 Asn21Asp G-25T I4 85 26 3.5 2.3 G-35C I4 85 1.2 0 0.01 # T307C E5 85 1.2 0 0.01 Phe103Leu C+139T I5 85 48.2 16.5 16.8 C+145T I5 85 2.4 0 0.01 G1199A E11 85 12.9 0 0.4 Ser400Asn C1236T E12 188 48.9 13.3 14.4 Gly412Gly # C+44T I12 188 11.7 0 0.4 T-76A I16 85 45.9 22.4 20.3 A+137G I17 85 1.2 0 0.01 G2677T E21 83b 43.4 42.2 38.4 Ala893Ser G2995A E24 36b 11.1 38.4 Ala999Thr C3435T E26 537 47.7 26.4 24.1 Ile1145Ile C3396T E26 188 0.53 0 0.01 Wobble § MDR1 sequences gb:AC002457 and AC005068 are defined as 'wild type`. Login to comment
108 The substitution of Phe by Leu at position 103 (exon 5) is located next to the second TMDs on the extracellular side that is close to the glycosylation sites of the protein. Login to comment

PMID: 11240981 [PubMed] Cascorbi I et al: "Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects."

No. Sentence Comment

79 Exon 5 T307C (Phe103Leu), which was found heterozygously in 2 individuals in our previous study,14 could not be identified in this large sample. Login to comment
95 With the use of a significantly larger sample of white volunteers, the previous data on allelic frequencies were confirmed, except for the Phe103Leu. Login to comment

PMID: 12065748 [PubMed] Kimchi-Sarfaty C et al: "Functional characterization of coding polymorphisms in the human MDR1 gene using a vaccinia virus expression system."

No. Sentence Comment

2 To determine whether common polymorphic forms of P-gp are likely to alter function of P-gp, we characterized five known MDR1 coding polymorphisms (N21D, F103L, S400N, A893S, and A998T) using a vaccinia virus-based transient expression system. Login to comment
20 In this study, we examined the five most common P-gp coding polymorphisms previously reported in the literature (N21D, F103L, S400N, A893S, and A998T). Login to comment
30 Using the technique described by Kunkel et al. (1987), five different mutated sites were introduced into the MDR1 gene with the following primers: for the N21D (A3G) polymorphism, 5Ј TTT TTC ACT TTT ATC GTT CAG TTT AA 3Ј; for the F103L (C3T) polymorphism, 5Ј CAG ATT CAT GAA GAG CCC TGT ATC A 3Ј; for the S400N (G3T) polymorphism, 5Ј TCG AGA TGG GTA ATT GAA GTG AAC AT 3Ј; for the A893S (G3T) polymorphism, 5Ј AGC GAT CTT CCC AGA ACC TTC TAG TT 3Ј; and for the A998T (G3A) polymorphism, 5Ј TAT TTT GGC TTT GGT ATA GTC AGG AGC 3Ј. Login to comment
48 We have chosen HeLa cells for these studies because of their low level of endogenous P-gp expression, their ability to express high TABLE 1 Common MDR1 polymorphisms that change amino acids Location Polymorphic Variant Heterozygous Frequency Reference Exon Nucleotide % 2 61 N21D 17.6 Hoffmeyer et al. (2000) 11.2 Cascorbi et al. (2001) 5.7 Decleves et al. (2000) 5 307 F103L 1.2 Hoffmeyer et al. (2000) 10 1107 G369P 0.2 Cascorbi et al. (2001) 11 1199 S400N 12.9 Hoffmeyer et al. (2000) 5.5 Cascorbi et al. (2001) A893S 43.0 Mickley et al. (1998) A893T 41.6 Cascorbi et al. (2001) 21 2677 A893S 62.0a , 13.0b Kim et al. (2001) A893G 56.4 Cascorbi et al. (2001) 24 2995 A998T 11.0 Mickley et al. (1998) a European Americans. b African Americans. levels of wild-type and mutant P-gp after vaccinia infection/ transfection, and their relative ease of transfection (Hrycyna et al., 1998; Ramachandra et al., 1998; Gribar et al., 2000). Login to comment
63 HeLa cells were infected/transfected with the pTM1-MDR1 vector harboring the MDR1 polymorphisms N21D, F103L, S400N, A893S, and A998T (described in Table 1). Login to comment
71 Discussion In this study a transient vaccinia expression system was used to determine the effect of five known coding human MDR1 polymorphisms on P-gp function: N21D, F103L, S400N, A893S, and A998T. Login to comment
113 Infected/transfected HeLa cells with wild-type pTM1-MDR1 (--), pTM1-MDR1-N21D (- -⅐- -⅐), pTM1-MDR1-F103L (⅐⅐⅐⅐), pTM1-MDR1-S400N (-⅐-⅐-), pTM1-MDR1-A998T (- - - -), and pTM1-MDR1-A893S (⅐⅐⅐-⅐⅐⅐) were incubated and analyzed by FACS as described under Materials and Methods, with MRK-16 or control IGg2a␬ monoclonal antibodies (-⅐-⅐-⅐) 13.5 h after infection/transfection. Login to comment
117 Cells were transfected with pTM1 (control), pTM1-MDR1, (wild-type P-gp), pTM1-MDR1- N21D, pTM1-MDR1-F103L, pTM1-MDR1-S400N, pTM1-MDR1-A893S, and pTM1-MDR1-A998T. Login to comment
119 with A, 0.5 ␮M Calcein-AM: wild-type (--), N21D (- -⅐- -⅐), and S400N (-⅐-⅐-), in the presence of an inhibitor, 5 ␮M cyclosporin A (- - -); B, 0.5 ␮M bodipy-FL-forskolin: wild-type (--), N21D (- -⅐- -⅐), F103L (⅐⅐⅐⅐), and S400N (-⅐-⅐-), in the presence of an inhibitor, 5 ␮M cyclosporin A (- - -); C, 0.5 ␮M bodipy-FL-verapamil: wild-type (--), N21D (- -⅐- -⅐), F103L (⅐⅐⅐⅐), and S400N (-⅐- ⅐-), in the presence of an inhibitor, 5 ␮M cyclosporin A (- - -); D, 0.1 ␮M bodipy-FL-paclitaxel: wild-type (--), A893S (- -⅐- -⅐), in the presence of an inhibitor, 5 ␮M cyclosporin A for the wild-type (- -), and for A893S (- - -). Login to comment

PMID: 12172213 [PubMed] Goto M et al: "C3435T polymorphism in the MDR1 gene affects the enterocyte expression level of CYP3A4 rather than Pgp in recipients of living-donor liver transplantation."

No. Sentence Comment

42 In the present study, the variants in exon 2 G-1A, A61G (Asn21 Asp) in exon 2, T307C (Phe103 Leu) in exon 5, G1199A (Ser400 Asn) in exon 11 and C+44T in intron 12 were not observed. Login to comment

PMID: 12357145 [PubMed] Lotsch J et al: "Does the A118G polymorphism at the mu-opioid receptor gene protect against morphine-6-glucuronide toxicity?"

No. Sentence Comment

106 33 T/T T/T MDR1 2 A61G Asn21Asp 11.2 20.6 9 A/G A/G Forward: 5Ј-AGG AGC AAA GAA GAA GAA CTT TTT TAA ACT GAT C-3Ј 9.3 17.6 8 Reverse: 5Ј-GAT TCC AAA GGC TAG CTT GC-3Ј 5 T307C Phe103Leu 0.6 1.2 9 T/T T/T Forward: 5Ј-GTG GTT GCA CAC AGT CAG CA-3Ј Reverse: 5Ј-GGA GGA TGT CTA ATT ACC TGG TCA-3Ј 11 G1199A Ser400Asn 5.5 11.1 9 G/G G/G Forward: 5Ј-CAG CTA TTC GAA GAG TGG GC-3Ј 6.5 12.9 8 Reverse: 5Ј-CCG TGA GAA AAA AAC TTC AAG G-3Ј 21 G2677T Ala893Ser 41.6 49.2 9 T/T T/T Forward: 5Ј-TGC AGG CTA TAG GTT CCA GG-3Ј 63.9 43.4 8 Reverse: 5Ј-GTT TGA CTC ACC TTC CCA G-3Ј 21 G2677A Ala893Thr 0.9 2 9 NA NA Forward: 5Ј-TGC AGG CTA TAG GTT CCA GG-3Ј Reverse: 5Ј-TTT AGT TTG ACT CAC CTT CCC G-3Ј 26 A3320C Gln1107Pro 0.2 0.4 9 A/A A/A 26 C3396T Ala1132Ala 0.3 0.5 8 C/C C/C Forward: 5Ј-ATC TGT GAA CTC TTG TTT TCA GC-3Ј 26 C3435T Ile1145Ile 50.3 47.7 8 T/T T/T Reverse: 5Ј-TCG ATG AAG GCA TGT ATG TTG-3Ј 53.9 50.5 9 - - MRP2 10 G1249A Val417Ile 12.5 20.8 34 G/G G/G Forward: 5Ј-GGG TCC TAA TTT CAA TCC TTA-3Ј Reverse: 5Ј-TAT TCT TCT GGG TGA CTT TTT-3Ј 18 C2302T Arg768Trp 1 2.1 34 C/C C/C Forward: 5Ј-GGA GTA GTG CTT AAT ATG AAT-3Ј 18 C2366T Ser789Phe 1 2.1 34 C/C C/C Reverse: 5Ј-CCC ACC CCA CCT TTA TAT CTT-3Ј 28 C3972T Ile132Ile 21.9 35.4 34 C/T C/T Forward: 5Ј-TGC TAC CCT TCT CCT GTT CTA-3Ј Reverse: 5Ј-ATC CAG GCC TTC CTT CAC TCC-3Ј 31 G4348A Ala1450Thr 1 2.1 34 G/G G/G Forward: 5Ј-AGG AGC TAA CAC ATG GTT GCT-3Ј Reverse: 5Ј-GGG TTA AGC CAT CCG TGT CAA-3Ј † Sequence is not translated. Login to comment

PMID: 12359865 [PubMed] Schwab M et al: "Genetic polymorphisms of the human MDR1 drug transporter."

No. Sentence Comment

50 Of the 15 identified SNPs, three polymorphisms resulted in protein alterations, one in exon 2 (Asn21Asp), in exon 5 (Phe103Leu), and in exon 11 (Ser400Asn). Login to comment
60 In a Northern Italian population, the extent of linkage disequilibrium TABLE 2 Summary of MDR1 genetic variants in different ethnic groups Location Position Allele Effect Reference promotor 5 flanking/-41a A (28) G exon 1a exon 1a/-145 C (28) G exon 1b exon 1b/-129 T (25, 33) C intron 1 exon 2/-4 C (29) T intron 1 exon 2/-1 G initiation of translation (25, 27, 29) A exon 2 exon 2/61 A Asn21Asp (25-27, 29) G intron 4 exon 5/-35 G (25) C intron 4 exon 5/-25 G (25) T exon 5 exon 5/307 T Phe103Leu (25) C intron 6 exon 6/+139 C (25, 27) T intron 6 exon 6/+145 C (25) T exon 7 exon 7/548 A Asn183Ser (29) G exon 11 exon 11/1199 G Ser400Asn (25, 27, 29) A exon 12 exon 12/1236 C wobble (23, 25, 27, 29) T (Gly412Gly) intron 12 exon 12/+44 C (25, 27) T exon 13 exon 13/1474 C Arg492Cys (29) T intron 16 exon 17/-76 T (25, 27) A intron 17 exon 17/137 A (25) G exon 21 exon 21/2650 C wobble (29) T (Leu884Leu) (Continued ) TABLE 2 (Continued) Location Position Allele Effect Reference exon 21 exon 21/2677 G (22, 23, 27, 29) T Ala893Ser A Ala893Thr exon 24 exon 24/2956 A Met986Val (33) G exon 24 exon 24/2995 G Ala999Thr (22) A exon 26 exon 26/3320 A Gln1107Pro (27) C exon 26 exon 26/3396 C wobble (25) T exon 26 exon 26/3421 T Ser1141Thr (29, 30) A exon 26 exon 26/3435 C wobble (23, 25, 29) T (Ile1145Ile) exon 28 exon 28/4030 G (33) C exon 28 exon 28/4036 A (23, 33) G The positions of the polymorphisms correspond to positions of MDR1 cDNA with the first base of the ATG start codon set to 1 (GenBank accession # M14758). Login to comment
69 The protein alteration Phe103Leu in exon 5 is located next to the second transmembrane domain on the extracellular side of P-glycoprotein and is in close vinicity to glycosylation sites of P-glycoprotein. Login to comment
86 However, a recent publication characterized the functional consequences of five coding SNPs (Asn21Asp, Phe103Leu, Ser400Asn, Ala893Ser, Ala999Thr) using a vaccinia virus-based transient expression system (40a). Login to comment

PMID: 12419946 [PubMed] Sakaeda T et al: "MDR1 genotype-related pharmacokinetics and pharmacodynamics."

No. Sentence Comment

56 In 2001, Hitzl et al. also indicated that healthy Caucasian subjects with T/T3435 had a more decreased efflux of rhodamine from CD56ϩ NK cells and a lower MDR1 mRNA expression in leukocytes than those with C/C3435 .65) In renal tissues, the C3435T polymorphism is reported to be associated with reduced MDR1 expression.31) However, Tanabe et al. suggested that C3435T had no effect on the placental MDR1 expression based on 89 subjects and Western blotting.53) We determined MDR1 mRNA levels in biopsy specimens of the duodenum obtained from 13 healthy Japanese subjects by real time quantitative RT-PCR and found that MDR1 mRNA expression was higher in T/T3435 than C/C3435 or C/T3435 (Fig. 1).66) The discrepancies between the reports might be ex- November 2002 1393 Table 2. Summary of Genetic Polymorphisms in MDR1 Position Location Effect A1a/-41G Intron Noncoding C-145G Exon 1a Noncoding T-129C (T12C) Exon 1b Noncoding C-4T Exon 2 Noncoding G-1A Exon 2 Noncoding A61G Exon 2 Asn21Asp G5/-25T Intron G5/-35C Intron T307C Exon 5 Phe103Leu C6/ϩ139T Intron A548G Exon 7 Asn183Ser G1199A Exon 11 Ser400Asn C1236T Exon 12 Silent C12/ϩ44T Intron C1474T Exon 13 Arg492Cys T17/-76A Intron A17/ϩ137G Intron C2650T Exon 21 Silent G2677(A,T) Exon 21 Ala893Thr (G2677A) Ala893Ser (G2677T) A2956G Exon 24 Met986Val G2995A Exon 24 Ala999Thr A3320C Exon 26 Gln1107Pro C3396T Exon 26 Silent T3421A Exon 26 Ser1141Thr C3435T Exon 26 Silent G4030C Exon 28 Silent A4036G Exon 28 Silent This list was based on the literature (refs. 49-54). Login to comment

PMID: 12769780 [PubMed] Toffoli G et al: "Pharmacogenetics of irinotecan."

No. Sentence Comment

261 Also T307C and G1199A are mutations causing a significant aminoacid change (Phe103Leu and Ser400Asn respectively) in important zones of the protein and possibly affecting the P-gp efficacy. Login to comment

PMID: 12831320 [PubMed] Sakaeda T et al: "Pharmacogenetics of MDR1 and its impact on the pharmacokinetics and pharmacodynamics of drugs."

No. Sentence Comment

75 Position Location Effect A1a/-41G Intron Non-coding C-145G Exon 1a Non-coding T-129C (T12C) Exon 1b Non-coding C-4T Exon 2 Non-coding G-1A Exon 2 Non-coding A61G Exon 2 Asn21Asp G5/-25T Intron G5/-35C Intron T307C Exon 5 Phe103Leu C6/+139T Intron A548G Exon 7 Asn183Ser G1199A Exon 11 Ser400Asn C1236T Exon 12 Silent C12/+44T Intron C1474T Exon 13 Arg492Cys T17/-76A Intron A17/+137G Intron C2650T Exon 21 Silent G2677(A,T) Exon 21 Ala893Thr (G2677A) Ala893Ser (G2677T) A2956G Exon 24 Met986Val G2995A Exon 24 Ala999Thr A3320C Exon 26 Gln1107Pro C3396T Exon 26 Silent T3421A Exon 26 Ser1141Thr C3435T Exon 26 Silent G4030C Exon 28 Silent A4036G Exon 28 Silent See references [34-39]. Login to comment

PMID: 12893986 [PubMed] Kroetz DL et al: "Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene."

No. Sentence Comment

301 Other non-synonymous variants (Asn21Asp, Phe103Leu, Ser400Asn, and Ala998Thr) have also been shown not to affect P-glycoprotein function [43]. Login to comment

PMID: 14576852 [PubMed] Ambudkar SV et al: "P-glycoprotein: from genomics to mechanism."

No. Sentence Comment

85 Kioka et al. (1989) showed a slight increase in resistance to doxorubicin, but no effect on colchicine or vinblastine Table 2 Common MDR1 exonic polymorphisms Exon number Polymorphic nucleotide variant Change in amino acid References 1 À145 - Ito et al. (2001) 1 À129 - Hoffmeyer et al. (2000); Tanabe et al. (2001) 2 61 N21D Cascorbi et al. (2001); Decleves et al. (2000); Hoffmeyer et al. (2000); Kim et al. (2001) 5 307 F103L Hoffmeyer et al. (2000) 7 548 N183S Kim et al. (2001) 10 1107 G369P Hoffmeyer et al. (2000) 11 1199 S400N Cascorbi et al. (2001); Hoffmeyer et al. (2000); Kim et al. (2001) 12 1236 Wobble Cascorbi et al. (2001); Hoffmeyer et al. (2000); Kim et al. (2001); Kioka et al. (1989) 13 1474 R492C Kim et al. (2001) 21 2650 Wobble Kim et al. (2001) 21 2677 893A, S, or T Cascorbi et al. (2001); Kim et al. (2001); Kioka et al. (1989); Mickley et al. (1998) 24 2956 M986V Tanabe et al. (2001) 24 2995 A999T Mickley et al. (1998) 26 3320 Q1107P Cascorbi et al. (2001) 26 3396 Wobble Hoffmeyer et al. (2000) 26 3421 S1141T Kim et al. (2001) 26a 3435 Wobble Hoffmeyer et al. (2000); Kim et al. (2001); Kioka et al. (1989) 28 4030 - Tanabe et al. (2001) 28 4036 - Kioka et al. (1989); Tanabe et al. (2001) a The only polymorphism that correlates with changes in drug delivery and disposition P-glycoprotein SV Ambudkar et al resistance in the SNP located on exon 21, position 2677, Ser893 (Kioka et al., 1989). Login to comment
110 HeLa cells were infected/transfected with empty vector (pTM1), wild-type pTM1-MDR1, pTM1-MDR1-S400N, pTM1-MDR1-N21D, pTM1-MDR1-F103L, pTM1-MDR1-A998T, and pTM1-MDR1-A893S, and were analysed by FACS as described previously (Kimchi-Sarfaty et al., 2002) Table 3 Selected substrates and modulators of P-glycoprotein Substrates Modulators Vinca alkaloids Calcium channel blockers Vinblastine Verapamil Vincristine Dihydropyridines Anthracyclines Antiarrhythmics Daunorubicin Quinine Doxorubicin Antihypertensives Antibiotics Reserpine Dactinomycin Antibiotics Actinomycin D Cephalosporins Other cytotoxic agents Immunosuppressants Mitomycin Cyclosporin A Taxol Steroid hormones Colchicine Progesterone Puromycin HIV protease inhibitors Digoxin Saquinavir Alcoholism treatment drug Disulfiram Phytochemical Curcumin Moreover, most of these studies correlated the manifestation of this polymorphism with a change in drug delivery or disposition. Login to comment

PMID: 14749689 [PubMed] Marzolini C et al: "Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance."

No. Sentence Comment

75 Summary of genetic polymorphisms in MDR1 Location Position Mutation Effect Mutant allele frequency (%) Hoffmeyer et al89 : C Cascorbi et al90 : C Siegmund et al91 : C Promotor 5' flanking/-41 A/G Noncoding Exon 1a Exon 1a/-145 C/G Noncoding Exon 1b Exon 1b/-129 T/C Noncoding 5.9 Intron 1 Exon 2/-4 C/T Noncoding Intron 1 Exon 2/-1 G/A Initial translation 5.6 9 3.7 Exon 2 Exon 2/61 A/G Asn21Asp 9.3 11.2 8.9 Intron 4 Exon 5/-35 G/C 0.6 Intron 4 Exon 5/-25 G/T 16.5 Exon 5 Exon 5/307 T/C Phe103Leu 0.6 0 Intron 6 Exon 6/ϩ139 C/T 40.6 37.2 35.8 Intron 6 Exon 6/ϩ145 C/T 1.2 Exon 7 Exon 7/548 A/G Asn183Ser Exon 11 Exon 11/1199 G/A Ser400Asn 6.5 5.5 2.9 Exon 12 Exon 12/1236 C/T Silent 37.8 41 34.3 Intron 12 Exon 12/ϩ44 C/T 5.9 4.9 7.5 Exon 13 Exon 13/1474 C/T Arg492Cys Intron 16 Exon 17/-76 T/A 45.3 46.2 49.3 Intron 17 Exon 17/ϩ137 A/G 0.6 Exon 21 Exon 21/2650 C/T Silent Exon 21 Exon 21/2677 G/T Ala893Ser 41.6 40.3 G/A Ala893Thr 1.9 3.7 Exon 24 Exon 24/2956 A/G Met986Val Exon 24 Exon 24/2995 G/A Ala999Thr Exon 26 Exon 26/3320 A/C Gln1107Pro 0.2 Exon 26 Exon 26/3396 C/T Silent 0.3 Exon 26 Exon 26/3421 T/A Ser1141Thr Exon 26 Exon 26/3435 C/T Silent 48.1 53.9 50.7 Exon 28 Exon 28/4030 G/C Exon 28 Exon 28/4036 A/G The positions of the polymorphisms were established with the first base of the ATG start codon set to 1. Login to comment

PMID: 15212152 [PubMed] Pauli-Magnus C et al: "Functional implications of genetic polymorphisms in the multidrug resistance gene MDR1 (ABCB1)."

No. Sentence Comment

94 A vaccinia virus expression system was used to examine the Asn21Asp, Phe103Leu, Ser400Ala, Ala893Ser, and Ala893Thr P-glycoprotein variants. Login to comment
118 Functional Impact in vitro of MDR1 Variants Amino acid change Functional effect of the variant allele Reference Val185Ser Increased colchicine resistance [30] ⌬Phe335 Decreased resistance to vinca alkaloids; no resistance to dactinomycin [31] Lys536Gln, Gly534Asp, Lys536Arg, Ser532Arg, ⌬Tyr490 Defective RNA processing [33] Ala893Ser Acquired overexpression of one allele in drug-resistant cells [20] Ala893Ser Decreased digoxin efflux [19] Asn21Asp, Phe103Leu, Ser400Ala, Ala893Ser, Ala893Thr No effect on P-glycoprotein cell surface expression and substrate specificity [69] Ala893Ser No difference in calcein-AM transport [27] Ala893Ser/Thr No difference in transport of verapamil, digoxin, viblastine and cyclosporine A [35] 3435 polymorphisms were analyzed separately, with AUC values being highest for individuals carrying the reference alleles. Login to comment

PMID: 15256718 [PubMed] Ishikawa T et al: "Pharmacogenomics of drug transporters: a new approach to functional analysis of the genetic polymorphisms of ABCB1 (P-glycoprotein/MDR1)."

No. Sentence Comment

79 For this purpose, the cDNA of ABCB1 was cloned from the human liver cDNA library, and several variant forms (i.e., N21D, N44S, F103L, G185V, S400N, A893S, A893T, M986V) were prepared by site-directed mutagenesis (see Fig. 4A for primers). Login to comment
94 The variant forms (i.e., N21D, N44S, F103L, G185V, S400N, A893S, A893T, M986V) exhibited the verapamil-enhanced ATPase activity, as did the wild type of ABCB1. Login to comment
118 Kinetic Parameters of the Wild Type and SNP Variants of ABCB1 Variant Km Vmax (mM) (nmol/min/mg protein) Wild type 2.190Ϯ0.150 13.14Ϯ1.95 N21D 0.502Ϯ0.126 45.26Ϯ11.33 N44S 0.580Ϯ0.148 31.03Ϯ4.65 F103L 1.100Ϯ0.078 36.34Ϯ8.33 G185V 0.831Ϯ0.102 56.76Ϯ6.76 S400N 0.327Ϯ0.025 13.74Ϯ2.08 A893S 0.441Ϯ0.042 17.24Ϯ6.72 A893T 0.904Ϯ0.244 10.77Ϯ1.35 M986V 0.419Ϯ0.062 22.69Ϯ6.84 The wild type and variants of ABCB1 were then expressed it in Sf9 cells using the pFASTBAC1 vector and recombinant baculoviruses. Login to comment

PMID: 15379652 [PubMed] Sakaeda T et al: "Pharmacogenetics of drug transporters and its impact on the pharmacotherapy."

No. Sentence Comment

127 Position Location Effect A1a/-41G intron noncoding C-145G exon 1a noncoding T-129C (T12C) exon 1b noncoding C-4T exon 2 noncoding G-1A exon 2 noncoding A61G G5/-25T G5/-35C exon 2 intron intron Asn21Asp T307C C6/+139T exon 5 intron Phe103Leu A548G exon 7 Asn183Ser G1199A exon 11 Ser400Asn C1236T C12/+44T exon 12 intron silent C1474T T17/-76A A17/+137G exon 13 intron intron Arg492Cys C2650T exon 21 silent G2677(A,T) exon 21 Ala893Thr (G2677A) Ala893Ser (G2677T) A2956G exon 24 Met986Val G2995A exon 24 Ala999Thr A3320C exon 26 Gln1107Pro C3396T exon 26 silent T3421A exon 26 Ser1141Thr C3435T exon 26 silent G4030C exon 28 silent A4036G exon 28 silent The list was based on the reports [67,68,71-74]. Login to comment

PMID: 15499164 [PubMed] Ishikawa T et al: "Functional evaluation of ABCB1 (P-glycoprotein) polymorphisms: high-speed screening and structure-activity relationship analyses."

No. Sentence Comment

78 For this purpose, the cDNA of ABCB1 was cloned from the human liver cDNA library, and several variant forms (i.e., N21D, N44S, F103L, G185V, S400N, A893S, A893T, M986V) were prepared by site-directed mutagenesis (see Fig. 2A for primers). Login to comment
86 The variant forms (i.e., N21D, N44S, F103L, G185V, S400N, A893S, A893T, M986V) exhibited the verapamil-enhanced ATPase activity, as did the wild type of ABCB1. Login to comment
105 Kinetic parameters of the wild type and SNP variants of ABCB1 Variant Km Vmax (mM) (nmolWminWmg protein) Wild type 2.190±0.150 13.14±1.95 N21D 0.502±0.126 45.26±11.33 N44S 0.580±0.148 31.03±4.65 F103L 1.100±0.078 36.34±8.33 G185V 0.831±0.102 56.76±6.76 S400N 0.327±0.025 13.74±2.08 A893S 0.441±0.042 17.24±6.72 A893T 0.904±0.244 10.77±1.35 M986V 0.419±0.062 22.69±6.84 The wild type and variants of ABCB1 were then expressed it in Sf9 cells using the pFASTBAC1 vector and recombinant baculoviruses. Login to comment

PMID: 15618700 [PubMed] Honda T et al: "Polymorphism of MDR1 gene in healthy japanese subjects: a novel SNP with an amino acid substitution (Glu108Lys)."

No. Sentence Comment

13 To date, the following SNPs in the MDR1 gene leading to amino acid substitutions have been identiˆed: A61G (Asn21Asp) in exon 2, T307C (Phe103Leu) in exon 5, G1199A (Ser400Asn) in exon 11, G2677T (Ala893Ser) in exon 21, G2677A (Ala893Thr) in exon 21 and A2956G (Met986Val) in exon 24. Login to comment

PMID: 15618713 [PubMed] Itoda M et al: "Twelve novel single nucleotide polymorphisms in ABCB1/MDR1 among Japanese patients with ventricular tachycardia who were administered amiodarone."

No. Sentence Comment

18 Much eort has been taken to uncover polymorphisms in the ABCB1WMDR1 gene since a synonymous SNP, which correlated with diminished MDR1 expression levels in the human duodenum, was reported by Homeyer et al.7) To date, information on 19 single nucleotide polymorphisms (SNPs) including 7 nonsynonymous ones (N21D, F103L, S400N, A893S, A893T, A999T and Q1107P) for ABCB1WMDR1 have been reported in Caucasians.8,9) ABCB1WMDR1 gene SNPs including intronic10) and 2 nonsynonymous SNPs (E108K, M986V)11,12) were also reported in Japanese population. Login to comment
78 Moreover, the reported nonsynonymous polymorphisms, N21D, F103L, S400N, A893S and A999T have been shown not to substantially aect the activity of P-glycoprotein14) . Login to comment

PMID: 16370938 [PubMed] Dey S et al: "Single nucleotide polymorphisms in human P-glycoprotein: its impact on drug delivery and disposition."

No. Sentence Comment

123 Location Position Mutation Effect Promoter 5`/-41 A→G Noncoding Exon 1a Exon 1a/-145 C→G Noncoding Exon 1b Exon 1b/-129 T→C Noncoding Intron 1 Exon 2/-4 C→T Noncoding Intron 1 Exon 2/-1 G→A Initiation of translation Exon 2 Exon 2/61 A→G Asn21Asp Intron 4 Exon 5/-35 G→C Intron 4 Exon 5/-25 G→T Exon 5 Exon 5/307 T→C Phe103Leu Intron 6 Exon 6/+139 C→T Intron 6 Exon 6/+145 C→T Exon 7 Exon 7/548 A→G Asn183Ser Exon 11 Exon 11/1119 G→A Ser400Asn Exon 12 Exon 12/1236 C→T Silent base change Intron 12 Exon 12/+44 C→T Exon 13 Exon 13/1474 C→T Arg492Cys Intron 16 Exon 17/-76 T→A Intron 17 Exon 17/+137 A→G Exon 21 Exon 21/2650 C→T Silent base change Exon 21 Exon 21/2677 G→T G→A Ala893Ser Ala893Thr Exon 24 Exon 24/2956 A→G Met986Val Exon 24 Exon 24/2995 G→A Ala999Thr Exon 26 Exon 26/3320 A→C Gln1107Pro Exon 26 Exon 26/3396 C→T Silent base change Exon 26 Exon 26/3421 T→A Ser1141Thr Exon 26 Exon 26/3435 C→T Silent base change Exon 28 Exon 28/4030 G→C Exon 28 Exon 28/4036 A→G The positions of the polymorphism are from the first base of the ATG start codon set to 1. Login to comment

PMID: 16415525 [PubMed] Sakaeda T et al: "MDR1 genotype-related pharmacokinetics: fact or fiction?"

No. Sentence Comment

29 Representative genetic polymorphisms in MDR1 Position Location EŠect A1aW-41G intron noncoding C-145G exon 1a noncoding T-129C (T12C) exon 1b noncoding C-4T exon 2 noncoding G-1A exon 2 noncoding A61G exon 2 Asn21Asp G5W-25T intron G5W-35C intron T307C exon 5 Phe103Leu C6W＋139T intron C6W＋145T intron A548G exon 7 Asn183Ser G1199A exon 11 Ser400Asn C1236T exon 12 silent C12W＋44T intron C1474T exon 13 Arg492Cys T17W-76A intron A17W＋137G intron C2650T exon 21 silent G2677A,T exon 21 Ala893Thr (G2677A) Ala893Ser (G2677T) A2956G exon 24 Met986Val G2995A exon 24 Ala999Thr A3320C exon 26 Gln1107Pro C3396T exon 26 silent T3421A exon 26 Ser1141Thr C3435T exon 26 silent G4030C exon 28 silent A4036G exon 28 silent See references 27, 32-36. Login to comment

PMID: 18287207 [PubMed] Gow JM et al: "Substrate-dependent effects of human ABCB1 coding polymorphisms."

No. Sentence Comment

206 In one study, the N21D, F103L, S400N, A893S, and A998T SNPs and three double mutants (N21N/S400N, N21D/A893S, and S400N/ A893S) were investigated using a vaccinia virus expression system with BODIPY-FL-paclitaxel, and no differences in function were noted among the variant and reference P-gps (Kimchi-Sarfaty et al., 2002). Login to comment

PMID: 18668431 [PubMed] Zhou SF et al: "Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition."

No. Sentence Comment

296 Exon 2 contains a polymorphism that changes Asn-21 to Asp, and the mutation at exon 5 changes Phe-103 to Leu. Login to comment

PMID: 20103563 [PubMed] Klaassen CD et al: "Xenobiotic, bile acid, and cholesterol transporters: function and regulation."

No. Sentence Comment

6832 Nucleotide Change Amino Acid Change In Vitro Function Protein Expression/ Localization ABCB1 MDR1 A61G N21D ↔ N.D. T307C F103L N.D. N.D. G1199A S400N 1↔ Normal C2005T R669C ↔ N.D. G2677T A893S 21↔ Normal G2677A A893T 1↔ Notmal T3421A S1141T 2↔ N.D. C3435T I1145I 2↔ N.D. G3751A V1251I 2 N.D. 2, reduced function; 1, increased function; ↔, no change in function; N.D. not determined. Login to comment

PMID: 19285158 [PubMed] Fung KL et al: "A synonymous polymorphism in a common MDR1 (ABCB1) haplotype shapes protein function."

No. Sentence Comment

152 A study in our lab showed that common polymorphisms of MDR1 at 61ANG (N21D), 307TNC (F103L), 1199GNA (S400N), 2677GNT (A893S) and 2995GNA (A999T) do not change the transport of four MDR1 substrates when expressed at high levels in human cells [66]. Login to comment
151 A study in our lab showed that common polymorphisms of MDR1 at 61ANG (N21D), 307TNC (F103L), 1199GNA (S400N), 2677GNT (A893S) and 2995GNA (A999T) do not change the transport of four MDR1 substrates when expressed at high levels in human cells [66]. Login to comment

PMID: 16529292 [PubMed] Li YH et al: "MDR1 gene polymorphisms and clinical relevance."

No. Sentence Comment

42 Table 1 Geneticpolymorphismsin MDRl ~~~~~~~~~~ Position Location Effect C-l4SG T-l29C(T12C) C-4T G-IA A61C G.51-2ST G.51-3SC T307C C6/+139C A548G G119YA C1236T c12li44T C1474T TIlJ-76A A 17/+137G C26SOT G2677T A2956G G2995A A3320C C3396T T342l A C343ST T3421A C343ST G4030C A4036G Intron Exon la Exon 1b Exon 2 Exon 2 Exon 2 lntron Intron Exon 5 Intron Exon 7 Exon 11 Exon 12 lntron Exon 13 Intron Intron Exon 21 Exon 21 Exon 21 Exon 24 Exon 24 Exon 26 Exon 26 Exon 26 Exon 26 Exon 28 Exon 26 Non-coding Non-coding Non-coding Non-coding Non-coding Am21Asp Phe103Leu Asnl83Ser Ser400Asn Wobble(Gly412Gly) Arg492Cys Wobble(Leu884Leu) Ala893Thr Ala893Ser Met986Val Ala999Thr Gln1I 07Pro Wobble Serll41Thr Wobble(1le114SIIe) Silent Silent In recent years, most of the MDR1 SNPs were identified, with some resulting in changes in P-gp . Login to comment
49 Table 1 Geneticpolymorphismsin MDRl ~~~~~~~~~~ Position Location Effect C-l4SG T-l29C(T12C) C-4T G-IA A61C G.51-2ST G.51-3SC T307C C6/+139C A548G G119YA C1236T c12li44T C1474T TIlJ-76A A 17/+137G C26SOT G2677T A2956G G2995A A3320C C3396T T342l A C343ST T3421A C343ST G4030C A4036G Intron Exon la Exon 1b Exon 2 Exon 2 Exon 2 lntron Intron Exon 5 Intron Exon 7 Exon 11 Exon 12 lntron Exon 13 Intron Intron Exon 21 Exon 21 Exon 21 Exon 24 Exon 24 Exon 26 Exon 26 Exon 26 Exon 26 Exon 28 Exon 26 Non-coding Non-coding Non-coding Non-coding Non-coding Am21Asp Phe103Leu Asnl83Ser Ser400Asn Wobble(Gly412Gly) Arg492Cys Wobble(Leu884Leu) Ala893Thr Ala893Ser Met986Val Ala999Thr Gln1I 07Pro Wobble Serll41Thr Wobble(1le114SIIe) Silent Silent In recent years, most of the MDR1 SNPs were identified, with some resulting in changes in P-gp . Login to comment

PMID: 12235446 [PubMed] Siegmund W et al: "Effect of levothyroxine administration on intestinal P-glycoprotein expression: consequences for drug disposition."

No. Sentence Comment

38 MDR1 genotyping The following 10 most frequent or putatively functional single nucleotide polymorphisms of the MDR1 gene were identified as described recently: exon 2 G-1A, A61G (amino acid exchange Asn21Asp), T307C (Phe103Leu), exon 6 Cϩ139T, G1199A (Ser400Asn), C1236T, exon 17 T-76A, G2677T/A (Ala893Ser/Thr), and C3435T.18 In brief, the deoxyribonucleic acid (DNA) of venous blood was extracted by use of a standard phenol-chloroform procedure. Login to comment

PMID: 11495756 [PubMed] Brinkmann U et al: "Pharmacogenetics of the human drug-transporter gene MDR1: impact of polymorphisms on pharmacotherapy."

No. Sentence Comment

68 Single nucleotide polymorphisms (SNPs) in the MDR1 gene SNP Region Number Frequency of SNPsa [%] Effect Heterozygous Homozygous Observed Estimated T-12C E1 85 11.8 0 0.4 Non-coding G-1A E2 188 11.2 0 0.4 Translation initiation A61G E2 188 17.6 0.5 0.81 Asn21Asp G-25T I4 85 26.0 3.5 2.3 G-35C I4 85 1.2 0 0.01 T307C E5 85 1.2 0 0.01 Phe103Leu C+139T I5 85 48.2 16.5 16.8 C+145T I5 85 2.4 0 0.01 G1199A E11 85 12.9 0 0.4 Ser400Asn C1236T E12 188 48.9 13.3 14.4 Gly412Gly C+44T I12 188 11.7 0 0.4 T-76A I16 85 45.9 22.4 20.3 A+137G I17 85 1.2 0 0.01 G2677T E21 83b 43.4 42.2 38.4 Ala893Ser G2995A E24 36b 11.1 0 Ala999Thr C3435T E26 537 47.7 26.4 24.1 Ile1145Ile C3396T E26 188 0.53 0 0.01 Wobble aMDR1 sequences Genbank (gb) accession numbers AC002457 and AC005068 are defined as wildtype. Login to comment

PMID: 15217301 [PubMed] Ieiri I et al: "The MDR1 (ABCB1) gene polymorphism and its clinical implications."

No. Sentence Comment

162 [94] Recently, a new mechanism for the drug- Sarfaty et al.[89] also investigated functional conse- grapefruit juice interaction has been reported; the quences of MDR1 polymorphisms (Asn21Asp, bioavailability and serum concentrations of fex- Phe103Leu, Ser400Asn, Ala893Ser, and ofenadine were reduced when grapefruit juice was Ala998Thr) using a vaccinia virus-based transient taken. Login to comment