Glutathione S-transferase omega 1 and omega 2 pharmacogenomics

Baidehi Mukherjee, Oreste E. Salavaggione, Linda L. Pelleymounter, Irene Moon, Bruce W. Eckloff, Daniel J Schaid, Eric D Wieben, Richard M Weinshilboum

Research output: Contribution to journalArticle

63 Citations (Scopus)

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 four 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 compared with wild type (WT), whereas 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, compared with WT, whereas the Ile41 and Asp142 allozymes displayed levels similar to that of WT GSTO2. Rabbit reticulocyte lysate 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.

Original languageEnglish (US)
Pages (from-to)1237-1246
Number of pages10
JournalDrug Metabolism and Disposition
Volume34
Issue number7
DOIs
StatePublished - 2006

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Pharmacogenetics
Glutathione Transferase
Isoenzymes
Polymorphism
Ethnic Groups
Codon
Single Nucleotide Polymorphism
Nucleotides
COS Cells
Reticulocytes
Arsenic
Biotransformation
Transfection
Genes
Western Blotting
Rabbits
Degradation
DNA
Enzymes
Proteins

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Glutathione S-transferase omega 1 and omega 2 pharmacogenomics. / Mukherjee, Baidehi; Salavaggione, Oreste E.; Pelleymounter, Linda L.; Moon, Irene; Eckloff, Bruce W.; Schaid, Daniel J; Wieben, Eric D; Weinshilboum, Richard M.

In: Drug Metabolism and Disposition, Vol. 34, No. 7, 2006, p. 1237-1246.

Research output: Contribution to journalArticle

Mukherjee B, Salavaggione OE, Pelleymounter LL, Moon I, Eckloff BW, Schaid DJ et al. Glutathione S-transferase omega 1 and omega 2 pharmacogenomics. Drug Metabolism and Disposition. 2006;34(7):1237-1246. https://doi.org/10.1124/dmd.106.009613
Mukherjee, Baidehi ; Salavaggione, Oreste E. ; Pelleymounter, Linda L. ; Moon, Irene ; Eckloff, Bruce W. ; Schaid, Daniel J ; Wieben, Eric D ; Weinshilboum, Richard M. / Glutathione S-transferase omega 1 and omega 2 pharmacogenomics. In: Drug Metabolism and Disposition. 2006 ; Vol. 34, No. 7. pp. 1237-1246.
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