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Molecular Consequences of Genetic Variations in the Glutathione Peroxidase 1 Selenoenzyme

¹ Department of Pathology and the ² Research Resources Center, University of Illinois at Chicago; ³ Northwestern University, Chicago, Illinois; ⁴ Division of Pediatrics, The Cleveland Clinic, Cleveland, Ohio; and ⁵ Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington

Requests for reprints: Alan M. Diamond, Department of Pathology, MC 847, University of Illinois at Chicago, 840 South Wood Street, Chicago, IL 60612. Phone: 312-413-8747; Fax: 312-996-7586; E-mail: adiamond{at}uic.edu.

Key Words: selenium • selenoproteins • glutathione peroxidase • polymorphisms

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. [Cancer Res 2009;69(20):8183–90]