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Identification of functionally variant MDR1 alleles among European Americans and African Americans
Author(s) -
Kim Richard B.,
Leake Brenda F.,
Choo Edna F.,
Dresser George K.,
Kubba Samir V.,
Schwarz Ute I.,
Taylor Amanda,
Xie HongGuang,
McKinsey Joel,
Zhou Sheng,
Lan LuBin,
Schuetz John D.,
Schuetz Erin G.,
Wilkinson Grant R.
Publication year - 2001
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1067/mcp.2001.117412
Subject(s) - nonsynonymous substitution , single nucleotide polymorphism , genetics , biology , allele , snp , genotype , exon , fexofenadine , population , gene , pharmacology , medicine , environmental health , genome
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 ( MDR1ast;2 ) and occurred in 62% of European Americans and 13% of African Americans. In vitro expression of MDR1 encoding Ala893 ( MDR1ast;1 ) or a site‐directed Ser893 mutation ( MDR1ast;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, MDR1ast;1 and MDR1ast;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 *2/*2 and the *1/*2 heterozygotes having an intermediate value, suggesting enhanced in vivo P‐glycoprotein activity among subjects with the MDR1ast;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. Clinical Pharmacology & Therapeutics (2001) 70 , 189–199; doi: 10.1067/mcp.2001.117412