Comparison of N-acetylcysteine and l-2-oxothiazolidine-4-carboxylate as cysteine deliverers and glutathione precursors in human malignant melanoma transplants in mice.
OBJECTIVE
Glutathione is an important cellular compound which affects detoxification of electrophiles and may have direct or indirect effects on pigment formation. It is therefore of importance to study interstitial concentrations in melanoma tissue while decreasing its formation with an enzyme inhibitor and increasing its amount with cysteine deliverers.


METHODS
Glutathione formation was inhibited by intraperitoneal (i.p.) injection of BSO. N-Acetylcysteine (NAC) and l-2-oxothiazolidine-4-carboxylate (OTC) were then given i.p. to subgroups of the animals. Intratumoral microdialysis was performed during BSO treatment, during BSO treatment combined with NAC or OTC and after discontinuation of BSO but ongoing NAC or OTC treatment.


RESULTS
Glutathione formation was inhibited during BSO treatment. The dialysate concentrations of both glutathione and cysteine decreased during concomitant treatment with BSO and NAC or OTC. Recovery of the amounts of the two compounds was seen in both groups after discontinuation of BSO treatment. In the NAC group we also observed an acute increase in dialysate concentrations of cysteine after NAC injection. The 5-S-cysteinyldopa concentrations were unaffected by variations in glutathione and cysteine concentrations.


CONCLUSIONS
5-S-Cysteinyldopa in melanoma is not formed from glutathione in vivo to any appreciable extent. The intracellular amount of cysteine is probably not a limiting factor for cysteinyldopa formation. It seems that both NAC and OTC can be used as cysteine deliverers to melanoma cells in vivo to produce recovery of glutathione levels after synthesis inhibition by BSO treatment.
Dizdar
N
N
Department of Clinical Chemistry, University Hospital, S-581 85 Linköping, Sweden. Nil.Dizdar@lio.se
Kullman
A
A
Kågedal
B
B
D000111:Acetylcysteine / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D003545:Cysteine / Q000187:drug effects / Q000378:metabolism*; D003548:Cysteinyldopa / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D017551:Microdialysis; D009368:Neoplasm Transplantation; D011498:Protein Precursors / Q000378:metabolism; D011761:Pyrrolidonecarboxylic Acid; D013844:Thiazoles / Q000378:metabolism / Q000494:pharmacology*; D053778:Thiazolidines; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D011498:Protein Precursors; D013844:Thiazoles; D053778:Thiazolidines; D003548:Cysteinyldopa; D019328:Buthionine Sulfoximine; D005978:Glutathione; D003545:Cysteine; D011761:Pyrrolidonecarboxylic Acid; D000111:Acetylcysteine; C029536:2-oxothiazolidine-4-carboxylic acid