ABCB1 p.Glu108Lys
| Predicted by SNAP2: | A: N (72%), C: N (53%), D: N (78%), F: D (53%), G: N (72%), H: N (57%), I: N (53%), K: N (61%), L: N (72%), M: N (57%), N: N (82%), P: D (75%), Q: N (87%), R: N (66%), S: N (78%), T: N (78%), V: N (78%), W: D (66%), Y: N (61%), |
| Predicted by PROVEAN: | A: D, C: D, D: N, F: D, G: D, H: D, I: D, K: N, L: D, M: D, N: D, P: D, Q: N, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Genetic polymorphisms of ATP-binding cassette tran... Expert Opin Pharmacother. 2005 Nov;6(14):2455-73. Sakurai A, Tamura A, Onishi Y, Ishikawa T
Genetic polymorphisms of ATP-binding cassette transporters ABCB1 and ABCG2: therapeutic implications.
Expert Opin Pharmacother. 2005 Nov;6(14):2455-73., [PMID:16259577]
Abstract [show]
Pharmacogenomics, the study of the influence of genetic factors on drug action, is increasingly important for predicting pharmacokinetics profiles and/or adverse reactions to drugs. Drug transporters, as well as drug metabolism play pivotal roles in determining the pharmacokinetic profiles of drugs and their overall pharmacological effects. There is an increasing number of reports addressing genetic polymorphisms of drug transporters. However, information regarding the functional impact of genetic polymorphisms in drug transporter genes is still limited. Detailed functional analysis in vitro may provide clear insight into the biochemical and therapeutic significance of genetic polymorphisms. This review addresses functional aspects of the genetic polymorphisms of human ATP-binding cassette transporters, ABCB1 and ABCG2, which are critically involved in the pharmacokinetics of drugs.
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No. Sentence 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].
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ABCB1 p.Glu108Lys 16259577:106:341
status: NEW129 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.
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ABCB1 p.Glu108Lys 16259577:129:25
status: NEW466 HONDA T, DAN Y, KOYABU N et al.: Polymorphism of MDR1 gene in healthy Japanese subjects: a novel SNP with an amino acid substitution (Glu108Lys).
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ABCB1 p.Glu108Lys 16259577:466:134
status: NEW437 HONDA T, DAN Y, KOYABU N et al.: Polymorphism of MDR1 gene in healthy Japanese subjects: a novel SNP with an amino acid substitution (Glu108Lys).
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ABCB1 p.Glu108Lys 16259577:437:134
status: NEW[hide] Polymorphism of MDR1 gene in healthy japanese subj... Drug Metab Pharmacokinet. 2002;17(5):479-81. Honda T, Dan Y, Koyabu N, Ieiri I, Otsubo K, Higuchi S, Ohtani H, Sawada Y
Polymorphism of MDR1 gene in healthy japanese subjects: a novel SNP with an amino acid substitution (Glu108Lys).
Drug Metab Pharmacokinet. 2002;17(5):479-81., [PMID:15618700]
Abstract [show]
We discovered a novel single nucleotide polymorphism (SNP) at position 325 (G325A) in exon 5 of the multidrug-resistance 1 (MDR1) gene in a study of 37 healthy Japanese subjects. Details are as follows. SNP, 020614Honda001; GENE NAME, human P-glycoprotein (MDR1); ACCESSION NUMBER, M29427; LENGTH, 25 bases; 5'-ATGAATCTGGAGG/AAAGACATGACCA-3'. This SNP is expected to cause an amino acid substitution (Glu108Lys). In this study, one homozygote and one heterozygote for G325A were identified.
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No. Sentence Comment
6 SNP15 (479) SNP Communication Polymorphism of MDR1 Gene in Healthy Japanese Subjects: A Novel SNP with an Amino Acid Substitution (Glu108Lys) Tomohiro HONDA1, Yukihiko DAN1, Noriko KOYABU1, Ichiro IEIRI2, Kenji OTSUBO2, Shun HIGUCHI3, Hisakazu OHTANI1 and Yasufumi SAWADA1 1Division of Biopharmaceutics, Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan 2Department of Hospital Pharmacy, Faculty of Medicine, Tottori University, Yonago, Japan 3Division of Clinical Pharmacokinetics, Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan Summary: We discovered a novel single nucleotide polymorphism (SNP) at position 325 (G325A) in exon 5 of the multidrug-resistance 1 (MDR1) gene in a study of 37 healthy Japanese subjects.
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ABCB1 p.Glu108Lys 15618700:6:131
status: NEW9 This SNP is expected to cause an amino acid substitution (Glu108Lys).
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ABCB1 p.Glu108Lys 15618700:9:58
status: NEW32 Subsequent sequence analysis revealed that these subjects were a homozygote and a heterozygote for a novel mutation in exon 5, G325A (Glu108Lys) (Fig. 1B).
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ABCB1 p.Glu108Lys 15618700:32:134
status: NEW39 This change of an anionic amino acid, glutamic acid, to a cationic amino acid residue, lysine, might in‰uence the function of P-gp. Although no studies have been conducted to elucidate the eŠect of amino acid substitution at position 108, mutant P-gp lacking the amino acid residues from 78 to 97 on the Ærst extracellular loop has been reported Novel MDR1 Gene Polymorphism G325A (Glu108Lys) SNP17 (481) to show altered ATPase activity in the presence of substrates.9) Site-directed mutations in transmembrane domains and ATP-binding domains often aŠect the extent of drug resistance, substrate speciˆcity and drug-stimulated ATPase activity.10-12) It was reported that the cells expressing Ser893-mutant (G2677T) P-gp exhibited lower digoxin accumulation than wild type MDR1.6) Some mutations were found to alter the susceptibility to P-gp inhibitors without aŠecting the substrate speciˆcity or transport kinetics of P-gp.12) Thus, it should be clariˆed whether the newly identiˆed SNP G325A (Glu108Lys) aŠects the transport activity of P-gp substrates and the susceptibility to P-gp inhibitors.
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ABCB1 p.Glu108Lys 15618700:39:401
status: NEWX
ABCB1 p.Glu108Lys 15618700:39:1051
status: NEW40 In conclusion, we found a novel SNP (G325A) of the MDR1 gene, leading to an amino acid substitution (Glu108Lys).
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ABCB1 p.Glu108Lys 15618700:40:101
status: NEW[hide] Twelve novel single nucleotide polymorphisms in AB... Drug Metab Pharmacokinet. 2002;17(6):566-71. Itoda M, Saito Y, Komamura K, Ueno K, Kamakura S, Ozawa S, Sawada J
Twelve novel single nucleotide polymorphisms in ABCB1/MDR1 among Japanese patients with ventricular tachycardia who were administered amiodarone.
Drug Metab Pharmacokinet. 2002;17(6):566-71., [PMID:15618713]
Abstract [show]
Twelve novel single nucleotide polymorphisms (SNPs) were found in the gene encoding the ATP-binding cassette transporter, P-glycoprotein, from 60 Japanese individuals who were administered the anti-antiarrythmic drug, amiodarone. The detected SNPs were as follows: 1) SNP, MPJ6_AB1017 (IVS6-109); GENE NAME, ABCB1; ACCESSION NUMBER, NT_017168; 2) SNP, MPJ6_AB1018 (IVS7+14); GENE NAME, ABCB1; ACCESSION NUMBER, NT_017168; 3) SNP, MPJ6_AB1021 (IVS9-44); GENE NAME, ABCB1; ACCESSION NUMBER, NT_017168; 4) SNP, MPJ6_AB1052 (IVS12+17); GENE NAME, ABCB1; ACCESSION NUMBER, NT_017168; 5) SNP, MPJ6_AB1029 (IVS15-69); GENE NAME, ABCB1; ACCESSION NUMBER, NT_017168; 6) SNP, MPJ6_AB1040 (IVS24+16); GENE NAME, ABCB1; ACCESSION NUMBER, NT_017168; 7) SNP, MPJ6_AB1053 (IVS27-189); GENE NAME, ABCB1; ACCESSION NUMBER, NT_017168; 8) SNP, MPJ6_AB1054 (IVS27-172); GENE NAME, ABCB1; ACCESSION NUMBER, NT_017168; 9) SNP, MPJ6_AB1048 (IVS27-167); GENE NAME, ABCB1; ACCESSION NUMBER, NT_017168; 10) SNP, MPJ6_AB1055 (IVS27-152); GENE NAME, ABCB1; ACCESSION NUMBER, NT_017168; 11) SNP, MPJ6_AB1049 (IVS27-119); GENE NAME, ABCB1; ACCESSION NUMBER, NT_017168; 12) SNP, MPJ6_AB1051 (at nucleotide 3751 (exon 28) from the A of the translation initiation codon); GENE NAME, ABCB1; ACCESSION NUMBER, NT_017168. Among these SNPs, only MPJ6_AB1051 resulted in an amino acid alteration, V1251I.
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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.
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ABCB1 p.Glu108Lys 15618713:18:493
status: NEW[hide] Detection of the four sequence variations of MDR1 ... Clin Biochem. 2003 Oct;36(7):511-8. Saito K, Miyake S, Moriya H, Yamazaki M, Itoh F, Imai K, Kurosawa N, Owada E, Miyamoto A
Detection of the four sequence variations of MDR1 gene using TaqMan MGB probe based real-time PCR and haplotype analysis in healthy Japanese subjects.
Clin Biochem. 2003 Oct;36(7):511-8., [PMID:14563443]
Abstract [show]
OBJECTIVES: P-glycoprotein (P-gp) is significant from the viewpoint of pharmacokinetics/pharmacodynamics (PK/PD). MDR1 gene encodes P-gp and has a wide variety of SNPs. As the SNPs may be one of the factors that induce pharmacogenetic individual difference, haplotype analysis is necessary to evaluate the PK/PD. DESIGN AND METHODS: The SNPs of the detected MDR1 were -129T>C, 325G>A, 2677G>T/A, and 3435C>T. For the analysis of linkage disequilibrium (LD) and haplotype analysis, and for the reconstruction of the haplotype pair, ARLEQUIN and PHASE were employed. RESULTS: The result of the chi(2) test detected significant LD between -129 and 2677, -129 and 3435, and 2677 and 3435. There were 9 haplotypes: T-G-C, T-T-C, C-T-C, T-A-C, C-A-C, T-G-T, T-T-T, C-G-T, and C-T-T. CONCLUSIONS: LD was found among the positions -129, 2677 and 3435. As a result, 9 haplotypes exists in the Japanese population. These results suggest that it would be necessary to give consideration to haplotype for the purpose of evaluating the PK/PD of the drugs transported by P-gp.
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No. Sentence Comment
29 In this respect, among the many SNPs of MDR1 already known, we focused on -129TϾC (5Ј flanking region), which is a regulatory SNP (rSNP), and 325GϾA (Glu108Lys) and 2677GϾT/A, which are nonsynonymous coding SNPs (cSNP).
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ABCB1 p.Glu108Lys 14563443:29:168
status: NEW194 Polymorphism of MDR1 gene on healthy Japanese subjects: A novel SNP with an amino acid substitution (Glu108Lys).
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ABCB1 p.Glu108Lys 14563443:194:101
status: NEW27 In this respect, among the many SNPs of MDR1 already known, we focused on afa;129Tb0e;C (5b18; flanking region), which is a regulatory SNP (rSNP), and 325Gb0e;A (Glu108Lys) and 2677Gb0e;T/A, which are nonsynonymous coding SNPs (cSNP).
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ABCB1 p.Glu108Lys 14563443:27:174
status: NEW188 [15] Honda T, Dan Y, Koyabu N, et al. Polymorphism of MDR1 gene on healthy Japanese subjects: A novel SNP with an amino acid substitution (Glu108Lys).
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ABCB1 p.Glu108Lys 14563443:188:139
status: NEW[hide] The MDR1 (ABCB1) gene polymorphism and its clinica... Clin Pharmacokinet. 2004;43(9):553-76. Ieiri I, Takane H, Otsubo K
The MDR1 (ABCB1) gene polymorphism and its clinical implications.
Clin Pharmacokinet. 2004;43(9):553-76., [PMID:15217301]
Abstract [show]
There has been an increasing appreciation of the role of drug transporters in the pharmacokinetic and pharmacodynamic profiles of certain drugs. Among various drug transporters, P-glycoprotein, the MDR1 gene product, is one of the best studied and characterised. P-glycoprotein is expressed in normal human tissues such as liver, kidney, intestine and the endothelial cells of the blood-brain barrier. Apical (or luminal) expression of P-glycoprotein in these tissues results in reduced drug absorption from the gastrointestinal tract, enhanced drug elimination into bile and urine, and impeded entry of certain drugs into the central nervous system. The clinical relevance of P-glycoprotein depends on the localisation in human tissues (i.e. vectorial or directional movement), the therapeutic index of the substrate drug and the inherent inter- and intra-individual variability. With regard to the variability, polymorphisms of the MDR1 gene have recently been reported to be associated with alterations in disposition kinetics and interaction profiles of clinically useful drugs, including digoxin, fexofenadine, ciclosporin and talinolol. In addition, polymorphism may play a role in patients who do not respond to drug treatment. Moreover, P-glycoprotein is an important prognostic factor in malignant diseases, such as tumours of the gastrointestinal tract.A growing number of preclinical and clinical studies have demonstrated that polymorphism of the MDR1 gene may be a factor in the overall outcome of pharmacotherapy for numerous diseases. We believe that further understanding the physiology and biochemistry of P-glycoprotein with respect to its genetic variations will be important to establish individualised pharmacotherapy with various clinically used drugs.
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No. Sentence Comment
66 Indeed, we recently observed a novel non-synonymous mutation (Glu108Lys) in Japanese subjects.
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ABCB1 p.Glu108Lys 15217301:66:62
status: NEW365 Overlapping substrate specifici- gene in healthy Japanese subjects: a novel SNP with an amino- ties and tissue distribution of cytochrome P4503A4 and p- acid substitution (Glu108Lys).
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ABCB1 p.Glu108Lys 15217301:365:172
status: NEW