Evidence for functionally significant polymorphism of human glutamate cysteine ligase catalytic subunit: Association with glutathione levels and drugresistance in the national cancer institute tumor cell line panel

Glutamate-cysteine ligase (GCL) is the first and rate-limiting enzyme invol ved in the biosynthesis of glutathione (GSH). The GCL heterodimer is encode d by two genes: GLCLC, which directs synthesis of the catalytic subunit, an d GLCLR, which encodes the regulatory subunit, We have previously identifie d a polymorphic GAG/CTC trinucleotide repeat within the 5 ' untranslated re gion of GLCLC. Here we report the further characterization of GLCLC polymor phism and the existence of five GLCLC alleles as defined by the trinucleoti de repeat, which exhibits a range of 4 to 10 uninterrupted repeats. Signifi cant variation in GLCLC allele frequencies was observed in four different e thnic populations examined. Interindividual variation in the capacity to pr oduce GSH due to GLCLC polymorphism is hypothesized to influence the cellul ar 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/res istance data was examined. Here we demonstrate an association between certa in GLCLC alleles and GSH levels and/or drug sensitivity, providing evidence that suggests polymorphism of human GLCLC is functionally significant.