Functional characterization of ABCC2 promoter polymorphisms and allele-specific expression

Area of Science:

• Pharmacogenomics
• Molecular Biology
• Genetics

Background:

• Multidrug resistance protein 2 (MRP2, ABCC2) is a key efflux transporter in the liver, kidney, and intestine.
• Its expression and function are crucial for drug disposition and detoxification.
• Interindividual variability in MRP2 function necessitates understanding the genetic basis of its expression.

Purpose of the Study:

• To identify and characterize functional polymorphisms in the ABCC2 promoter region.
• To investigate the impact of these variants on ABCC2 gene expression.
• To explore allele-specific expression as a mechanism for observed pharmacokinetic variations.

Main Methods:

• Resequencing of the ABCC2 promoter region (1.6 kb upstream) in 247 ethnically diverse DNA samples.
• Luciferase reporter gene assays to assess promoter activity of identified polymorphisms.
• Analysis of allele-specific mRNA expression in heterozygous human liver samples.

Main Results:

• Twelve ABCC2 promoter polymorphisms were identified.
• The -24C>T variant, alone and in a common haplotype, significantly increased ABCC2 promoter activity by 35%.
• Preferential transcription of the 3972C allele over the 3972T allele was observed in heterozygous liver samples, particularly with promoter/untranslated region variants.

Conclusions:

• The ABCC2 -24C>T polymorphism and associated haplotypes are functional, enhancing promoter activity.
• Allele-specific transcription contributes to interindividual differences in ABCC2 expression.
• Further research is needed to elucidate mechanisms underlying ABCC2 expression variability and MRP2 function.