Toxicological Sciences 61, 218-223 (2001)
Copyright © 2001 by the Society of Toxicology
BIOTRANSFORMATION AND TOXICOKINETICS |
Evidence for Functionally Significant Polymorphism of Human Glutamate Cysteine Ligase Catalytic Subunit: Association with Glutathione Levels and Drug Resistance in the National Cancer Institute Tumor Cell Line Panel
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* Laboratory of Clinical and Experimental Endocrinology and Immunology, Wadsworth Center, Albany, New York 12201;
Department of Biomedical Sciences, School of Public Health, State University of New York, Albany, New York 12222;
Laboratory of Structural Pathology, Wadsworth Center, Albany, New York 12201; and
Department of Biometry and Statistics, School of Public Health, State University of New York, Albany, New York 12222
Glutamate-cysteine ligase (GCL) is the first and rate-limiting enzyme involved in the biosynthesis of glutathione (GSH). The GCL heterodimer is encoded by two genes: GLCLC, which directs synthesis of the catalytic subunit, and GLCLR, which encodes the regulatory subunit. We have previously identified a polymorphic GAG/CTC trinucleotide repeat within the 5' untranslated region of GLCLC. Here we report the further characterization of GLCLC polymorphism and the existence of five GLCLC alleles as defined by the trinucleotide repeat, which exhibits a range of 4 to 10 uninterrupted repeats. Significant variation in GLCLC allele frequencies was observed in four different ethnic populations examined. Interindividual variation in the capacity to produce GSH due to GLCLC polymorphism is hypothesized to influence the cellular response to environmental toxicants and chemotherapeutic agents. To test this hypothesis, the 60 tumor cell lines of the National Cancer Institute drug screening panel were genotyped for the GLCLC trinucleotide repeat, and the association of GLCLC genotype with GSH levels and drug sensitivity/resistance data was examined. Here we demonstrate an association between certain GLCLC alleles and GSH levels and/or drug sensitivity, providing evidence that suggests polymorphism of human GLCLC is functionally significant.
Key Words: glutamate-cysteine ligase; GCL; GLCLC; polymorphism; trinucleotide repeat; glutathione; drug resistance.
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