Journal Article

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

Anne C. Walsh, J. Amelia Feulner and Andrew Reilly

in Toxicological Sciences

Volume 61, issue 2, pages 218-223
Published in print June 2001 | ISSN: 1096-6080
Published online June 2001 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/61.2.218
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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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.

Keywords: glutamate-cysteine ligase; GCL; GLCLC; polymorphism; trinucleotide repeat; glutathione; drug resistance

Journal Article.  4904 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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