TY - JOUR
T1 - Functional significance of the GAG trinucleotide-repeat polymorphism in the gene for the catalytic subunit of γ-glutamylcysteine ligase
AU - Nichenametla, Sailendra N.
AU - Ellison, Irina
AU - Calcagnotto, Ana
AU - Lazarus, Philip
AU - Muscat, Joshua
AU - Richie, John
N1 - Funding Information:
This study was supported in part by USPHS Grants P01CA68384 and K07CA104231. We thank Dr. Thomas Spratt for his assistance with 32 P scanning.
PY - 2008/9/1
Y1 - 2008/9/1
N2 - 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.
AB - 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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U2 - 10.1016/j.freeradbiomed.2008.05.012
DO - 10.1016/j.freeradbiomed.2008.05.012
M3 - Article
C2 - 18549827
AN - SCOPUS:48449091602
SN - 0891-5849
VL - 45
SP - 645
EP - 650
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
IS - 5
ER -