Functional significance of the GAG trinucleotide-repeat polymorphism in the gene for the catalytic subunit of gamma-glutamylcysteine ligase.
Gamma-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.
Cancer Prevention and Control Program, Penn State Cancer Institute, Department of Public Health Sciences, Penn State University College of Medicine, Hershey, PA 17033, USA.
Sailendra N
SN
Nichenametla
Irina
I
Ellison
Ana
A
Calcagnotto
Philip
P
Lazarus
Josh E
JE
Muscat
John P
JP
Richie
D000293:Adolescent; D000328:Adult; D000483:Alleles; D020134:Catalytic Domain; D004151:Dipeptides / Q000235:genetics*; D005260:Female; D015750:Genes, gag / Q000235:genetics*; D005838:Genotype; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism*; D005978:Glutathione / Q000097:blood; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D018911:Trinucleotide Repeats / Q000235:genetics*
D004151:Dipeptides; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; C017341:gamma-glutamylcysteine