title: Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo.
abstract: To evaluate whether alterations in the multidrug-resistance (MDR)-1 gene correlate with intestinal MDR-1 expression and uptake of orally administered P-glycoprotein (PGP) substrates, we analyzed the MDR-1 sequence in 21 volunteers whose PGP expression and function in the duodenum had been determined by Western blots and quantitative immunohistology (n = 21) or by plasma concentrations after orally administered digoxin (n = 8 + 14). We observed a significant correlation of a polymorphism in exon 26 (C3435T) of MDR-1 with expression levels and function of MDR-1. Individuals homozygous for this polymorphism had significantly lower duodenal MDR-1 expression and the highest digoxin plasma levels. Homozygosity for this variant was observed in 24% of our sample population (n = 188). This polymorphism is expected to affect the absorption and tissue concentrations of numerous other substrates of MDR-1.
authors.affiliation: Epidauros Biotechnology, Pharmacogenetics Laboratory, Am Neuland 1, D-82347 Bernried, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Hoffmeyer
authors.forename: O
authors.initials: O
authors.lastname: Burk
authors.forename: O
authors.initials: O
authors.lastname: von Richter
authors.forename: H P
authors.initials: HP
authors.lastname: Arnold
authors.forename: J
authors.initials: J
authors.lastname: Brockmöller
authors.forename: A
authors.initials: A
authors.lastname: Johne
authors.forename: I
authors.initials: I
authors.lastname: Cascorbi
authors.forename: T
authors.initials: T
authors.lastname: Gerloff
authors.forename: I
authors.initials: I
authors.lastname: Roots
authors.forename: M
authors.initials: M
authors.lastname: Eichelbaum
authors.forename: U
authors.initials: U
authors.lastname: Brinkmann
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000483:Alleles; D001483:Base Sequence; D004247:DNA; D005091:Exons; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D011110:Polymorphism, Genetic; D012689:Sequence Homology, Nucleic Acid
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004247:DNA