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Research ArticleArticle

Association of Breast Cancer Resistance Protein/ABCG2 Phenotypes and Novel Promoter and Intron 1 Single Nucleotide Polymorphisms

Balasubramanian Poonkuzhali, Jatinder Lamba, Stephen Strom, Alex Sparreboom, Kenneth Thummel, Paul Watkins and Erin Schuetz
Drug Metabolism and Disposition April 2008, 36 (4) 780-795; DOI: https://doi.org/10.1124/dmd.107.018366
Balasubramanian Poonkuzhali
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Jatinder Lamba
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Stephen Strom
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Alex Sparreboom
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Kenneth Thummel
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Paul Watkins
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Erin Schuetz
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Abstract

The hypothesis was tested that sequence diversity in breast cancer resistance protein (BCRP)'s cis-regulatory region is a significant determinant of BCRP expression. The BCRP promoter and intron 1 were resequenced in lymphoblast DNA from the polymorphism discovery resource (PDR) 44 subset. BCRP single nucleotide polymorphisms (SNPs) were genotyped in donor human livers, intestines, and lymphoblasts quantitatively phenotyped for BCRP mRNA expression. Carriers of the –15622C>T SNP had lower BCRP expression in multiple tissues. The intron 1 SNP 16702C>T was associated with high expression in livers; 1143G>A was associated with low expression in intestine; 12283T>C was associated with higher expression in the PDR44 and White livers. The –15994C>T promoter SNP was significantly associated with higher BCRP expression in multiple tissues. Patients with the –15994C>T genotype had substantially higher clearance of p.o. imatinib. We next determined whether BCRP expression was related to polymorphic alternative splicing or alternative promoter use. Liver polymorphically expressed an alternatively spliced mRNA [splice variant (SV) 1] skipping exon 2. Although SV1+ livers did not uniformly carry the exon 2 G34A allele, 90% of G34A livers expressed SV1 (versus 4% of 34GG livers). BCRP mRNA was significantly lower among Hispanic livers with the G34A variant genotype and may be due, in part, to polymorphic exon 2 splicing. Analysis of allele expression imbalance (AEI) showed that PDR44 samples with AEI had lower BCRP mRNA expression; however, no linked cis-polymorphisms were identified. BCRP used multiple promoters, and livers differentially using alternative exon 1b had lower BCRP. In conclusion, BCRP expression in lymphoblasts, liver, and intestine is associated with novel promoter and intron 1 SNPs.

  • Received August 16, 2007.
  • Accepted January 3, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (4)
Drug Metabolism and Disposition
Vol. 36, Issue 4
1 Apr 2008
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Research ArticleArticle

Association of Breast Cancer Resistance Protein/ABCG2 Phenotypes and Novel Promoter and Intron 1 Single Nucleotide Polymorphisms

Balasubramanian Poonkuzhali, Jatinder Lamba, Stephen Strom, Alex Sparreboom, Kenneth Thummel, Paul Watkins and Erin Schuetz
Drug Metabolism and Disposition April 1, 2008, 36 (4) 780-795; DOI: https://doi.org/10.1124/dmd.107.018366

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Research ArticleArticle

Association of Breast Cancer Resistance Protein/ABCG2 Phenotypes and Novel Promoter and Intron 1 Single Nucleotide Polymorphisms

Balasubramanian Poonkuzhali, Jatinder Lamba, Stephen Strom, Alex Sparreboom, Kenneth Thummel, Paul Watkins and Erin Schuetz
Drug Metabolism and Disposition April 1, 2008, 36 (4) 780-795; DOI: https://doi.org/10.1124/dmd.107.018366
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