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Effect of MRP2 and MRP3 Polymorphisms on Anastrozole Glucuronidation and MRP2 and MRP3 Gene Expression in Normal

Vineetha Koroth Edavana1, Rosalind B Penney2, Aiwei Yao-Borengasser1

  • 1Division of Medical Genetics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, USA.

International Journal of Cancer Research and Molecular Mechanisms
|March 18, 2016
PubMed

Insights

Genetic variations in MRP2 influence anastrozole glucuronidation, impacting breast cancer treatment response. This study highlights MRP2 single nucleotide polymorphisms (SNPs) as key factors in anastrozole metabolism.

Area of Science:

  • Pharmacogenomics
  • Drug Metabolism
  • Oncology

Background:

  • Anastrozole, an aromatase inhibitor, is crucial for breast cancer adjuvant therapy.
  • Its metabolism involves direct glucuronidation by UDP-glucuronosyltransferase1A4 (UGT1A4).
  • Interindividual variability in anastrozole glucuronidation may stem from genetic factors like UGT1A4 single nucleotide polymorphisms (SNPs) and transporter gene interactions.

Purpose of the Study:

  • To investigate the hypothesis that genetic variability in multidrug resistance-associated proteins (MRPs) influences anastrozole glucuronidation.
  • To analyze correlations between UGT1A4, MRP2, and MRP3 gene expressions and anastrozole glucuronidation in human liver samples.

Main Methods:

  • Correlation analysis of UGT1A4 and MRP2/MRP3 gene expressions.
  • Analysis of mRNA levels of MRP2 and MRP3 in relation to anastrozole glucuronidation.
  • Investigation of the association between specific MRP2 and MRP3 SNPs and their respective mRNA expressions and anastrozole glucuronidation.

Main Results:

  • MRP2 and MRP3 mRNA levels significantly correlated with UGT1A4 mRNA, anastrozole glucuronidation, and each other (p<0.05).
  • MRP2 SNPs showed a positive correlation with MRP2 mRNA expression.
  • Significant correlations were found between specific MRP2 SNPs (3972C>T, 2366C>T, -24C>T) and anastrozole glucuronidation (p<0.05).

Conclusions:

  • MRP2 genetic variability, specifically certain SNPs, plays a role in anastrozole metabolism.
  • These MRP2 SNPs may contribute to interindividual variations in anastrozole treatment response.
  • This is the first study to identify MRP2 SNPs as influencing anastrozole metabolism.
Keywords:
Anastrozole GlucuronidationMRP2 PolymorphismsMRP2 gene expressionMRP3 PolymorphismsMRP3 gene expression

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