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Potential role of UGT1A4 promoter SNPs in anastrozole pharmacogenomics

Vineetha Koroth Edavana1, Ishwori B Dhakal, Suzanne Williams

  • 1Division of Medical Genetics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.

Drug Metabolism and Disposition: the Biological Fate of Chemicals
|February 2, 2013
PubMed

Insights

Anastrozole glucuronidation varies significantly between individuals due to UGT1A4 genetic differences. This variability in anastrozole metabolism may impact breast cancer treatment effectiveness.

Area of Science:

  • Pharmacogenomics
  • Drug Metabolism
  • Oncology

Background:

  • Anastrozole, a third-generation aromatase inhibitor, shows improved efficacy and toxicity compared to tamoxifen for breast cancer.
  • Anastrozole undergoes Phase I oxidation and Phase II glucuronidation, primarily via UDP-glucuronosyltransferase 1A4 (UGT1A4).
  • Significant inter-individual variability exists in anastrozole pharmacokinetics, yet pharmacogenomic data are limited.

Purpose of the Study:

  • To investigate individual variability in anastrozole glucuronidation.
  • To explore the association between this variability and UGT1A4 gene polymorphisms.
  • To understand the implications for anastrozole response in breast cancer treatment.

Main Methods:

  • In vitro assays using liver microsomal preparations from 96 individuals.
  • Assessed anastrozole and lamotrigine glucuronidation, UGT1A4 mRNA expression, and UGT1A4 promoter polymorphisms.
  • Utilized recombinant UGT1A4 and a specific inhibitor (hecogenin) to confirm enzyme activity.

Main Results:

  • Demonstrated a 235-fold variability in anastrozole glucuronidation among subjects.
  • Anastrozole glucuronidation strongly correlated with lamotrigine glucuronidation and UGT1A4 mRNA levels.
  • UGT1A4 promoter polymorphisms (-163G

Conclusions:

  • Variability in anastrozole glucuronidation, influenced by UGT1A4 genetic variations, is a significant factor in its metabolism.
  • These findings suggest a potential link between UGT1A4 genotype and anastrozole response in breast cancer patients.
  • Further pharmacogenomic studies are warranted to optimize anastrozole therapy.

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