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; Josh E Muscat; John P Richie

doi:10.1016/j.freeradbiomed.2008.05.012

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

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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, Josh E Muscat and John P Richie

Free radical biology & medicine, Vol.45(5), pp.645-650

2008

DOI: https://doi.org/10.1016/j.freeradbiomed.2008.05.012

Handle:

https://hdl.handle.net/2376/116109

PMCID: PMC2562218

PMID: 18549827

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https://doi.org/10.1016/j.freeradbiomed.2008.05.012View

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Abstract

GCL activity

GAG trinucleotide repeat polymorphism

γ-Glutamylcysteine ligase

Short tandem repeat polymorphism

Glutathione

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.

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Title: Functional significance of the GAG trinucleotide-repeat polymorphism in the gene for the catalytic subunit of γ-glutamylcysteine ligase
Creators: Sailendra N Nichenametla - Cancer Prevention and Control Program, Penn State Cancer Institute, Department of Public Health Sciences, Penn State University College of Medicine, Hershey, PA 17033, USA
Irina Ellison - Department of Biology, St. Francis College, Brooklyn Heights, NY 11201, USA
Ana Calcagnotto - Cancer Prevention and Control Program, Penn State Cancer Institute, Department of Public Health Sciences, Penn State University College of Medicine, Hershey, PA 17033, USA
Philip Lazarus - Department of Pharmacology, Penn State University College of Medicine, Hershey, PA 17033, USA
Josh E Muscat - Cancer Prevention and Control Program, Penn State Cancer Institute, Department of Public Health Sciences, Penn State University College of Medicine, Hershey, PA 17033, USA
John P Richie - Cancer Prevention and Control Program, Penn State Cancer Institute, Department of Public Health Sciences, Penn State University College of Medicine, Hershey, PA 17033, USA
Publication Details: Free radical biology & medicine, Vol.45(5), pp.645-650
Academic Unit: Pharmaceutical Sciences, Department of
Publisher: Elsevier Inc
Identifiers: 99900548011801842
Language: English
Resource Type: Journal article