Received for publication February 3, 2006.
Revised April 19, 2006.
Accepted for publication April 19, 2006.

Glutathione S-Transferase Omega 1 and Omega 2 Pharmacogenomics

Abstract

Glutathione S-transferase omega 1 and omega 2 (GSTO1 and GSTO2) catalyze monomethyl arsenate reduction, the rate-limiting reaction in arsenic biotransformation. As a step toward pharmacogenomic studies of these phase II enzymes, we resequenced human GSTO1 and GSTO2 using DNA samples from four ethnic groups. We identified 31 and 66 polymorphisms in GSTO1 and GSTO2, respectively, with 4 nonsynonymous coding single nucleotide polymorphisms (cSNPs) in each gene. There were striking variations among ethnic groups in polymorphism frequencies and types. Expression constructs were created for all eight nonsynonymous cSNPs as well as a deletion of codon 155 in GSTO1, and those constructs were used to transfect COS-1 cells. Quantitative Western blot analysis, after correction for transfection efficiency, showed a reduction in protein level of greater than 50% for the GSTO1 Tyr32 variant allozyme when compared with wild type (WT), while levels for the Asp140, Lys208, Val236 and codon 155 deletion variant constructs were similar to that of the WT. For GSTO2, the Tyr130 and Ile158 variant allozymes showed 50% and 84% reductions in levels of expression, respectively, when compared to WT, while the Ile41 and Asp142 allozymes displayed levels similar to that of WT GSTO2. Rabbit reticulocyte lysate (RRL) degradation studies showed that the GSTO1 Tyr32 and the GSTO2 Tyr130, Ile158 and Asp142/Ile158 variant allozymes were degraded more rapidly than were their respective WT allozymes. These observations raise the possibility of functionally significant pharmacogenomic variation in the expression and function of GSTO1 and GSTO2.

Key words: glutathione transferases, pharmacogenetics, pharmacogenomics

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