Abstract:
OBJECTIVES:To evaluate whether ABCC2 gene polymorphisms are associated with expression and/or function of the efflux pump. METHODS:We investigated the allele frequency of ABCC2 -24C>T, -23G>A, c.1249G>A, c.1446C>G, c.1457C>T, c.2302C>T, c.2366C>T, c.3542G>T, c.3561G>A, c.3563T>A, c.3972C>T, c.4348G>A, and 4544G>A in 374 nonrelated German healthy volunteers and determined the impact on duodenal mRNA and protein content of ABCC2. For functional analysis, the disposition of intravenously (30 mg) and orally administered talinolol (100 mg) was measured among 31 individuals. Moreover, the effects of rifampicin-type induction (600 mg, 8 days) of duodenal ABCC2 were quantified in 22 participants with regard to genetic polymorphisms. RESULTS:The allele frequencies were 18.3% (-24T), 21.1% (1249A), 1.4% (1446G), 0.1% (3542T), 4.5% (3563A), 34.2% (3972T), and 4.4% (4544A); carriers of -23G>A, 1457C>T, 2302C>T, 2366C>T, 3561G>A, and 4348G>A were not identified. The -24T allele was in strong linkage with 3972T, and 3563A with 4544A, whereas 1249A was weakly linked with other variant alleles. None of the single nucleotide polymorphisms investigated influenced significantly intestinal ABCC2 mRNA and protein content. The variant ABCC2 1249G>A (V417I), however, was associated with lower oral bioavailability (P=0.001), and increased residual clearance of intravenous talinolol (P=0.021). Intestinal ABCC2 mRNA and protein expression were upregulated by rifampicin treatment, a genetic influence could be detected in only four cases heterozygote for 3563T>A or 4544G>A. CONCLUSION:The 1249G>A (V417I) polymorphism is obviously associated with higher activity of the intestinal transporter.
journal_name
Pharmacogenet Genomicsjournal_title
Pharmacogenetics and genomicsauthors
Haenisch S,May K,Wegner D,Caliebe A,Cascorbi I,Siegmund Wdoi
10.1097/FPC.0b013e3282f974b7subject
Has Abstractpub_date
2008-04-01 00:00:00pages
357-65issue
4eissn
1744-6872issn
1744-6880pii
01213011-200804000-00009journal_volume
18pub_type
杂志文章abstract:OBJECTIVES:Epidemiological studies documented associations between single nucleotide polymorphisms (SNPs) in the nucleotide excision repair gene XPD/ERCC2 and cancer risk. Little is known, however, about the underlying mechanisms for these associations. We explored a novel mechanism that could further explain the repor...
journal_title:Pharmacogenetics and genomics
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journal_title:Pharmacogenetics and genomics
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pub_type: 临床试验,杂志文章,多中心研究
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pub_type: 杂志文章,随机对照试验
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更新日期:2005-01-01 00:00:00
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doi:10.1097/FPC.0b013e3280e1cc92
更新日期:2007-09-01 00:00:00
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更新日期:2017-11-01 00:00:00
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更新日期:2008-06-01 00:00:00
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更新日期:2012-03-01 00:00:00
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更新日期:2005-09-01 00:00:00