ABCMdb

PMID: 12419946

Sakaeda T, Nakamura T, Okumura K
MDR1 genotype-related pharmacokinetics and pharmacodynamics.
Biol Pharm Bull. 2002 Nov;25(11):1391-400., [PubMed]

Sentences

No. Mutations Sentence Comment

38 ABCB1 p.Gly185Val The first report on the polymorphisms of the MDR1 gene was presented in 1989.47) MDR1 was isolated from human normal adrenal glands, and the deduced amino acid sequencing indicated two amino acid substitutions of Gly185Val and Ala893Ser, the latter suggested reflecting a genetic polymorphism. Login to comment 52 ABCB1 p.Asn183Ser ABCB1 p.Ser400Asn ABCB1 p.Asn21Asp ABCB1 p.Ser1141Thr ABCB1 p.Arg492Cys Kim et al. defined 15 alleles based on the frequencies of 11 polymorphisms of C-4T (noncoding), G-1A (noncoding), A61G (Asn21Asp), A548G (Asn183Ser), G1199A (Ser400Asn), C1236T (silent), C1474T (Arg492Cys), C2650T (silent), G2677T (Ala893Ser), T3421A (Ser1141Thr) and C3435T (silent).54) Six of 11 accompanied an amino acid change, and the others were conservative mutations. Login to comment 56 ABCB1 p.Asn183Ser ABCB1 p.Ser400Asn ABCB1 p.Asn21Asp ABCB1 p.Gln1107Pro ABCB1 p.Phe103Leu ABCB1 p.Ala999Thr ABCB1 p.Ser1141Thr ABCB1 p.Arg492Cys ABCB1 p.Met986Val 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 61 ABCB1 p.Ser400Asn ABCB1 p.Ser400Asn ABCB1 p.Asn21Asp ABCB1 p.Asn21Asp Kim et al. indicated that cells transduced with a variant MDR1 containing Ser893 showed a reduced intracellular accumulation of [3 H]-digoxin compared with cells with the wild-type Ala893 , suggesting enhanced efflux by the polymorphism of Ala893Ser (G2677T).54) On the other hand, very recently, Kimchi-Sarfaty et al. indicated that the cell surface expression and function of double mutants including the more common polymorphisms (A61G (Asn21Asp) and G1199A (Ser400Asn), A61G (Asn21Asp) and G2677T (Ala893Ser), G1199A (Ser400Asn) and G2677T (Ala893Ser)) showed no differences from the wild-type.67) MDR1 Genotype-Related Pharmacokinetics The aim of the clinical study by Greiner et al.64) was to elucidate the role of intestinal MDR1 expression in the interaction of digoxin with rifampin, and plasma concentration-time profiles were monitored after oral and intravenous administration of digoxin at 1 mg before and after oral administration of rifampin once daily for 16 d. Using the digoxin plasma concentration data after MDR1 induction by rifampin, Hoffmeyer et al.50) suggested that intestinal absorption of digoxin was greater in the subjects with the T-allele at position 3435. Login to comment