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

Abstract

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. 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 degrees 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. 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.