ABCMdb

PMID: 15618700

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., [PubMed]

Sentences

No. Mutations Sentence Comment

6 ABCB1 p.Glu108Lys 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. Login to comment 9 ABCB1 p.Glu108Lys This SNP is expected to cause an amino acid substitution (Glu108Lys). Login to comment 13 ABCB1 p.Ser400Asn ABCB1 p.Asn21Asp ABCB1 p.Phe103Leu ABCB1 p.Met986Val 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 32 ABCB1 p.Glu108Lys Subsequent sequence analysis revealed that these subjects were a homozygote and a heterozygote for a novel mutation in exon 5, G325A (Glu108Lys) (Fig. 1B). Login to comment 39 ABCB1 p.Glu108Lys ABCB1 p.Glu108Lys 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. Login to comment 40 ABCB1 p.Glu108Lys In conclusion, we found a novel SNP (G325A) of the MDR1 gene, leading to an amino acid substitution (Glu108Lys). Login to comment