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Molecular consequences of genetic variations in the glutathione peroxidase 1 selenoenzyme.

ABSTRACT: Accumulating data have implicated the selenium-containing cytosolic glutathione peroxidase, GPx-1, as a determinant of cancer risk and a mediator of the chemopreventive properties of selenium. Genetic variants of GPx-1 have been shown to be associated with cancer risk for several types of malignancies. To investigate the relationship between GPx-1 enzyme activity and genotype, we measured GPx-1 enzyme activity and protein levels in human lymphocytes as a function of the presence of two common variations: a leucine/proline polymorphism at codon 198 and a variable number of alanine-repeat codons. Differences in GPx activity among these cell lines, as well as in the response to the low-level supplementation of the media with selenium, indicated that factors other than just genotype are significant in determining activity. To restrict the study to genotypic effects, human MCF-7 cells were engineered to exclusively express allelic variants representing a combination of either a codon 198 leucine or proline and either 5 or 7 alanine-repeat codons following transfection of GPx-1 expression constructs. Transfectants were selected and analyzed for GPx-1 enzyme activity and protein levels. GPx-1 with 5 alanines and a leucine at codon 198 showed a significantly higher induction when cells were incubated with selenium and showed a distinct pattern of thermal denaturation as compared with GPx-1 encoded by the other examined alleles. The collective data obtained using both lymphocytes and MCF-7 indicate that both intrinsic and extrinsic factors cooperate to ultimately determine the levels of this enzyme available to protect cells against DNA damage and mutagenesis.

SUBMITTER: Zhuo P

PROVIDER: S-EPMC2763328 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Molecular consequences of genetic variations in the glutathione peroxidase 1 selenoenzyme.

Zhuo Pin P Goldberg Marci M Herman Lauren L Lee Bao-Shiang BS Wang Hengbing H Brown Rhonda L RL Foster Charles B CB Peters Ulrike U Diamond Alan M AM

Cancer research 20091013 20

Accumulating data have implicated the selenium-containing cytosolic glutathione peroxidase, GPx-1, as a determinant of cancer risk and a mediator of the chemopreventive properties of selenium. Genetic variants of GPx-1 have been shown to be associated with cancer risk for several types of malignancies. To investigate the relationship between GPx-1 enzyme activity and genotype, we measured GPx-1 enzyme activity and protein levels in human lymphocytes as a function of the presence of two common va ...[more]

PMID: 19826042

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Project description:PurposeThe antioxidant enzymes pathway is considered the most important pathway involved in the repair of reactive oxygen species (ROS)-induced damage. Therefore, we investigate the possible association between polymorphisms of Cu/Zn superoxide dismutase (SOD1), catalase (CAT), and glutathione peroxidase (GPX) genes and age -related cataract development.MethodsThe study included 415 cataract patients (121 patients with cortical, 109 with nuclear, 59 with posterior subcapsular, and 126 with mixed type) and 386 healthy control group of similar age. Genotyping of SOD1-251A/G, CAT-21A/T, and GPX1-198C/T was done by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. Differences in the frequencies were estimated using the χ(2) test and risk was estimated with an unconditional logistic regression after adjusting for age and gender.ResultsSOD1 G/G genotype frequency was significantly higher in cataract patients (p=0.012, OR=1.642, 95% CI=1.129-2.389). SOD1 A/A genotypes (p=0.001, OR=0.613, 95% CI=0.461-0.817) seem to have a protective role against cataract, and the G allele (p=0.001, OR=1.479, 95% CI=1.208-1.810) plays a dangeous effect against in the development of cataract. In CAT-21A/T and GPX1-198C/T polymorphisms, there were no significant differences in the variant homozygous frequencies in patients compared to controls (p=0.226, OR=1.358, 95% CI=0.839-2.199; p=0.521, OR=1.205, 95% CI=0.726-2.001, respectively). Stratification by the subtypes revealed that association between SOD polymorphism and cataract was in cortical and mixed type cataract. The genotype frequency of the GG and AA of SOD1-251A/G was significantly different in cortical and mixed type cataract group (p=0.031; OR: 1.805, 95% CI: 1.076-3.026; p=0.002; OR: 2.229, 95% CI: 1.364-3.645; p=0.026; OR: 0.608, 95% CI: 0.396-0.933; p=0.001; OR: 0.474, 95% CI: 0.305-0.734, respectively) compared to healthy controls.ConclusionsResults suggest that the G/G genotype of the SOD1-251A/G polymorphism may be associated with an increased risk of cataract. However, in CAT-21A/T and GPX1-198C/T polymorphisms, there were no significant differences in the variant homozygous frequencies in patients compared to controls.

Project description:BackgroundGlutathione (GSH) is one of the most important agents of the antioxidant defense system of the cell because, in conjunction with the enzymes glutathione peroxidase (GSH-Px) and glutathione S transferase pi (GSTpi), it plays a central role in the detoxification and biotransformation of chemotherapeutic drugs. This study evaluated the expression of GSH and the GSH-Px and GSTpi enzymes by immunohistochemistry in 30 canine mammary tumors, relating the clinicopathological parameters, clinical outcome and survival of the bitches. In an in vitro study, the expression of the genes glutamate cysteine ligase (GCLC) and glutathione synthetase (GSS) that synthesize GSH and GSH-Px gene were verified by qPCR and subjected to treatment with doxorubicin, to check the resistance of cancer cells to chemotherapy.ResultsThe immunohistochemical expression of GSH, GSH-Px and GSTpi was compared with the clinical and pathological characteristics and the clinical outcome in the bitches, including metastasis and death.The results showed that high immunoexpression of GSH was correlated to the absence of tumor ulceration and was present in dogs without metastasis (P < 0.05). There was significant correlation of survival with the increase of GSH (P < 0.05). The expression of the GSH-Px and GSTpi enzymes showed no statistically significant correlation with the analyzed variables (p > 0.05). The analysis of the relative expression of genes responsible for the synthesis of GSH (GCLC and GSS) and GSH-Px by quantitative PCR was done with cultured cells of 10 tumor fragments from dogs with mammary tumors.The culture cells showed a decrease in GCLC and GSS expression when compared with no treated cells (P < 0.05). High GSH immunoexpression was associated with better clinical outcomes.ConclusionTherefore, high expression of the GSH seems to play an important role in the clinical outcome of patients with mammary tumors and suggest its use as prognostic marker. The in vitro doxorubicin treatment significantly reduces the expression of GCLC and GSS genes so we can consider them to be candidates for predictive markers of therapeutic response in mammary cancer.

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Molecular consequences of genetic variations in the glutathione peroxidase 1 selenoenzyme.

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Molecular consequences of genetic variations in the glutathione peroxidase 1 selenoenzyme.

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