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Influence of polymorphisms of ABCB1 and ABCC2 on mRNA and protein expression in normal and cancerous kidney cortex

S Haenisch1, U Zimmermann, E Dazert

  • 1Institute of Pharmacology, University Hospital Schleswig-Holstein, Kiel, Germany.

The Pharmacogenomics Journal
|June 22, 2006
PubMed

Insights

Genetic variations in ABCB1 and ABCC2 transporters influence their expression in healthy kidney tissue, potentially affecting drug elimination. These transporter gene polymorphisms did not correlate with renal cell carcinoma tissue expression.

Area of Science:

  • Pharmacogenomics
  • Molecular Biology
  • Oncology

Background:

  • Single-nucleotide polymorphisms (SNPs) in adenosine 5' triphosphate (ATP) membrane transporters ABCB1 (P-glycoprotein, MDR1) and ABCC2 (multidrug resistance-associated protein (MRP2)) are implicated in drug transport.
  • The specific impact of ABCC2 SNPs on kidney drug elimination and renal cell carcinoma (RCC) etiology remains poorly understood.

Purpose of the Study:

  • To investigate the role of ABCB1 and ABCC2 genetic polymorphisms in kidney drug elimination and renal cell carcinoma.
  • To determine the expression levels of ABCB1 and ABCC2 mRNA and proteins in renal cell carcinoma and adjacent normal kidney tissues.

Main Methods:

  • Real-time PCR and immunohistochemistry were used to quantify ABCB1 and ABCC2 mRNA and protein expression in 82 RCC patients.
  • DNA genotyping was performed for specific ABCB1 and ABCC2 SNPs.
  • Reporter gene assays were conducted in HepG2 cells to assess the functional impact of ABCC2 variants.

Main Results:

  • ABCB1 and ABCC2 mRNA and protein levels were significantly lower in clear-cell RCC (CCRCC) compared to normal kidney cortex.
  • ABCB1 SNPs (2677T/A, 3435T) and ABCC2 SNP (-24C>T) were associated with altered mRNA expression levels in unaffected renal cortex.
  • No significant association was found between ABCB1/ABCC2 genotypes and their expression levels in RCC tissue.
  • The ABCC2 -24T variant demonstrated reduced activity in a reporter gene assay.

Conclusions:

  • ABCB1 and ABCC2 genotypes modulate transporter expression in the unaffected renal cortex, potentially influencing inter-individual drug and xenobiotic elimination.
  • The direct role of these genetic variants in RCC susceptibility or chemotherapy resistance requires further investigation.

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