Identification of functionally variant MDR1 alleles among European Americans and African Americans

被引:826
作者
Kim, RB [1 ]
Leake, BF
Choo, EF
Dresser, GK
Kubba, SV
Schwarz, UI
Taylor, A
Xie, HG
McKinsey, J
Zhou, S
Lan, LB
Schuetz, JD
Schuetz, EG
Wilkinson, GR
机构
[1] Vanderbilt Univ, Div Clin Pharmacol, Sch Med, Dept Med, Nashville, TN 37232 USA
[2] Vanderbilt Univ, Dept Pharmacol, Sch Med, Nashville, TN 37232 USA
[3] St Jude Childrens Res Hosp, Memphis, TN 38105 USA
关键词
D O I
10.1067/mcp.2001.117412
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
MDR1 (P-glycoprotein) is an important factor in the disposition of many drugs, and the involved processes often exhibit considerable interindividual variability that may be genetically determined. Single-strand conformational polymorphism analysis and direct sequencing of exonic MDR1 deoxyribonucleic acid from 37 healthy European American and 23 healthy African American subjects identified 10 single nucleotide polymorphisms (SNPs), including 6 nonsynonymous variants, occurring in various allelic combinations. Population frequencies of the 15 identified alleles varied according to racial background. Two synonymous SNPs (C1236T in exon 12 and C3435T in exon 26) and a nonsynonymous SNP (G2677T, Ala893Ser) in exon 21 were found to be linked (MDR1*2) and occurred in 62% of European Americans and 13% of African Americans. In vitro expression of MDR1 encoding Ala893 (MDR1*1) or a site-directed Ser893 mutation (MDR1*2) indicated enhanced efflux of digoxin by cells expressing the MDR1-Ser893 variant. In vivo functional relevance of this SNP was assessed with the known P-glycoprotein drug substrate fexofenadine as a probe of the transporter's activity. In humans, MDR1*1 and MDR1*2 variants were associated with differences in fexofenadine levels, consistent with the in vitro data, with the area under the plasma level-time curve being almost 40% greater in the *1/*1 genotype compared with the and the *1/*2 heterozygotes having an intermediate value, suggesting enhanced in vivo P-glycoprotein activity among subjects with the MDR1*2 allele. Thus allelic variation in MDR1 is more common than previously recognized and involves multiple SNPs whose allelic frequencies vary between populations, and some of these SNPs are associated with altered P-glycoprotein function.
引用
收藏
页码:189 / 199
页数:11
相关论文
共 35 条
[1]   Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration [J].
Allikmets, R ;
Shroyer, NF ;
Singh, N ;
Seddon, JM ;
Lewis, RA ;
Bernstein, PS ;
Peiffer, A ;
Zabriskie, NA ;
Li, YX ;
Hutchinson, A ;
Dean, M ;
Lupski, JR ;
Leppert, M .
SCIENCE, 1997, 277 (5333) :1805-1807
[2]   Biochemical, cellular, and pharmacological aspects of the multidrug transporter [J].
Ambudkar, SV ;
Dey, S ;
Hrycyna, CA ;
Ramachandra, M ;
Pastan, I ;
Gottesman, MM .
ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, 1999, 39 :361-398
[3]   Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency [J].
Brooks-Wilson, A ;
Marcil, M ;
Clee, SM ;
Zhang, LH ;
Roomp, K ;
van Dam, M ;
Yu, L ;
Brewer, C ;
Collins, JA ;
Molhuizen, HOF ;
Loubser, O ;
Ouelette, BFF ;
Fichter, K ;
Ashbourne-Excoffon, KJD ;
Sensen, CW ;
Scherer, S ;
Mott, S ;
Denis, M ;
Martindale, D ;
Frohlich, J ;
Morgan, K ;
Koop, B ;
Pimstone, S ;
Kastelein, JJP ;
Genest, J ;
Hayden, MR .
NATURE GENETICS, 1999, 22 (04) :336-345
[4]  
CARDARELLI CO, 1995, CANCER RES, V55, P1086
[5]  
CHAMBERS TC, 1993, J BIOL CHEM, V268, P4592
[6]  
CHEN CJ, 1990, J BIOL CHEM, V265, P506
[7]   DETERMINATION OF TERFENADINE AND TERFENADINE ACID METABOLITE IN PLASMA USING SOLID-PHASE EXTRACTION AND HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHY WITH FLUORESCENCE DETECTION [J].
COUTANT, JE ;
WESTMARK, PA ;
NARDELLA, PA ;
WALTER, SM ;
OKERHOLM, RA .
JOURNAL OF CHROMATOGRAPHY-BIOMEDICAL APPLICATIONS, 1991, 570 (01) :139-148
[8]  
CURRIER SJ, 1989, J BIOL CHEM, V264, P14376
[9]  
Cvetkovic M, 1999, DRUG METAB DISPOS, V27, P866
[10]  
FELLAY J, 2001, 8 C RETR OPP INF 200