γ-Glutamyl transpeptidase and its role in melanogenesis:: Redox reactions and regulation of tyrosinase

Metabolism of glutathione by gamma-glutamyl transpeptidase (gamma-GT) at the level of cell membrane has been shown to generate hydrogen peroxide in many cell types including human melanomas. gamma-GT does not appear to be involved in cysteine uptake for pheomelanin production in melanoma cells and does not contribute significantly to the pheomelanin synthesized in B16 melanoma cells. We have therefore examined the possibility of gamma-GT mediated production of prooxidant reactions and its effect, if any, on pigmentation using B16 melanoma cells. Our results indicate that in B16 melanoma cells, gamma-GT activity leads to the production of hydrogen peroxide. We further show that the nuclear levels of the redox sensitive transcription factor NF-kappaB is regulated by H2O2 formed by the action of gamma-GT: stimulation and inhibition of gamma-GT affect the levels of NF-kappaB. Tumor necrosis factor alpha, a hypopigmenting cytokine, known to activate NF-kappaB also up-regulates the gamma-GT messenger RNA and activity. Stimulation of gamma-GT generated prooxidant reactions led to a decrease in tyrosinase activity. We therefore propose that prooxidant reactions mediated by gamma-GT in turn regulate the levels of tyrosinase in pigment cells. Our findings thus introduce a new aspect in the regulation of pigmentation and ascribe a novel role for gamma-GT in pigment cells.