Polymorphism of glutathione transferase Omega 1 in a population exposed to a high environmental arsenic burden

Leiliane Paiva, Ricard Marcos, Amadeu Creus, Marjorie Coggan, Aaron J. Oakley, Philip G. Board

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33 Citations (Scopus)

Abstract

OBJECTIVES AND METHODS: The aim of this study was to investigate genetic variation in glutathione transferase omega 1 (GSTO1-1) in Atacameños, an indigenous population from Chile that has been exposed to environmental arsenic for many generations. GSTO1-1 is thought to catalyse the rate-limiting step in the biotransformation of arsenic in humans and may modulate the response of cancer patients to arsenic trioxide therapy. Allele frequencies were determined by PCR-based methods and a polymorphic variant (GSTO1-1 Val236) was expressed in Escherichia coli and functionally characterized. Urinary arsenic profiles were determined by inductive coupled plasma/mass spectrometry. RESULTS: A novel allele resulting in an Ala236Val substitution that has not been functionally characterized was detected in Atacameños and Chilean participants at a frequency of 0.033 and 0.009, respectively. The Val236 isoenzyme has diminished specific activity (10-20%) with a range of substrates. This loss of activity appears to result from a decrease in the kcat. The Val236 variant is also unstable and rapidly loses activity during purification or when heated at 45°C. The percent of inorganic arsenic in the urine of 205 Chilean participants showed a bimodal distribution that was not associated with the Ala140Asp, Glu155del or Ala236Val polymorphisms in GSTO1-1. CONCLUSION: It is likely that heterozygotes inheriting the Val236 variant subunit would have a partial deficiency of GSTO1-1 activity. Despite their effects on enzyme function the known variants of GSTO1-1 do not appear to explain the observed variability in the excretion of inorganic arsenic. © 2008 Lippincott Williams & Wilkins, Inc.
Original languageEnglish
Pages (from-to)1-10
JournalPharmacogenetics and Genomics
Volume18
DOIs
Publication statusPublished - 1 Jan 2008

Keywords

  • Arsenic biotransformation
  • Glutathione transferase omega
  • Polymorphisms
  • Urinary arsenic

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