Functional significance of the GAG trinucleotide-repeat polymorphism in the gene for the catalytic subunit of γ-glutamylcysteine ligase

Sailendra N. Nichenametla, Irina Ellison, Ana Calcagnotto, Philip Lazarus, Joshua Muscat, John Richie

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

γ-Glutamylcysteine ligase (GCL) is the rate-limiting enzyme in glutathione (GSH) synthesis. A GAG-repeat polymorphism in the 5′ UTR of the gene coding for the catalytic subunit of GCL (GCLC) has been associated with altered GSH levels in vitro. Thus, we hypothesized that this polymorphism is associated with altered GCL activity and blood GSH levels in vivo. A total of 256 healthy United States black and white adults were genotyped for the GAG polymorphism and blood GSH levels were measured. In a subset of 107 individuals, blood GCL activity was determined. Five alleles with 4, 7, 8, 9, and 10 GAG repeats were observed. The most prevalent genotype was 7/9 (40%) followed by 7/7 (32%) and 9/9 (11%). GSH levels were 15% lower in 9/9 individuals than 7/9 individuals (P = 0.05). GCL activity was 21% lower in 9/9 individuals than 7/7 individuals (P = 0.04). A decreasing trend of GCL activity was observed in the order of 7/7 > 7/9 > 9/9 (P = 0.04). These findings show that 9/9 individuals have lower blood GSH levels, which is likely due to a decrease in GCL activity. Such individuals might be more susceptible to oxidative stress-related diseases than individuals with other genotypes.

Original languageEnglish (US)
Pages (from-to)645-650
Number of pages6
JournalFree Radical Biology and Medicine
Volume45
Issue number5
DOIs
StatePublished - Sep 1 2008

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology (medical)

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