Opposite regulation of tyrosinase and glutathione peroxidase by intracellular thiols in human melanoma cells.
Conditions of oxidative stress lead to down-regulation of glutathione (GSH) and glutathione peroxidase (GPO), which could be responsible for tyrosinase induction in pigment cells. To address this question, the effects of selective modulation of GSH metabolism on melanogenic parameters of slightly and highly melanized melanoma cells were examined. Under standard culture conditions (100 microM cystine, 100 microM tyrosine), the levels of GSH and the activities of glutathione reductase (GR) and GPO were found to be directly related to the pigmentation of melanoma cells. Exposure to 50 microM buthionine sulfoximine for 72 h decreased tyrosinase activity by 30-50% and GSH levels by more than 95%. In contrast, inhibition of GR activity with bis(chloroethyl)nitrosourea or stimulation of GPO activity with sodium selenite did not affect tyrosinase activity nor pigment formation in the melanoma cells tested. Since cysteine (CysH) is a precursor of the GSH tripeptide, the modulation of tyrosinase and GPO activity by the extracellular cystine concentration was also examined. When the cystine concentration was increased from 0 to 200 microM, a dose-dependent decrease in tyrosinase activity was associated with dose-dependent increases in GPO activity and in cell levels of CysH and GSH. The results indicate that cellular thiols coregulate the activities of tyrosinase and GPO in opposite directions. These interdependent processes could provide melanoma cells with protection against oxidative stress at low as well as at high thiol concentration.
Benathan
M
M
Department of Dermatology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002330:Carmustine / Q000494:pharmacology; D003545:Cysteine / Q000378:metabolism; D003553:Cystine / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism*; D006801:Humans; D008543:Melanins / Q000378:metabolism; D008545:Melanoma / Q000201:enzymology / Q000378:metabolism*; D014442:Monophenol Monooxygenase / Q000378:metabolism*; D018384:Oxidative Stress; D018038:Sodium Selenite / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D008543:Melanins; D013438:Sulfhydryl Compounds; D003553:Cystine; D019328:Buthionine Sulfoximine; D005979:Glutathione Peroxidase; D014442:Monophenol Monooxygenase; D005978:Glutathione; D018038:Sodium Selenite; D003545:Cysteine; D002330:Carmustine