Role of copper and ceruloplasmin in oxidative mutagenesis induced by the glutathione-gamma-glutamyl transpeptidase system and by other thiols.
Glutathione is activated to a mutagen by gamma-glutamyl transpeptidase. Other thiols, such as cysteine, penicillamine, cysteine ethylester, and cysteinylglycine, are direct mutagens in the Ames Salmonella mutagenicity test. Thiol mutagenesis is oxidative in nature and involves H2O2 and possibly hydroxyl radicals. Transition metals are crucial for thiol autoxidation. The role of copper and ceruloplasmin (CP) in thiol-dependent mutagenesis was studied in Salmonella typhimurium strain TA102. Cu and CP at low concentrations enhanced thiol-dependent mutagenesis in the presence, but not in the absence, of added Fe. The degree of enhancement depended on the type of thiol. At high Cu or CP concentrations, thiol mutagenesis was inhibited. Cu also decreased the mutagenicity of H2O2. Cu- and CP-enhanced mutagenesis were inhibited by radical scavengers, catalase, and peroxidase but not by superoxide dismutase. The effects of Cu and CP on thiol-dependent mutagenesis were similar to their effects on thiol-driven lipid peroxidation. The results indicate that the role of Cu and CP in the enhancement of thiol mutagenesis is the facilitation of the transfer of electrons from a thiol to iron, rather than in catalysis of the Fenton reaction.
Stark
A A
AA
Department of Biochemistry, Tel-Aviv University, Ramat-Aviv, Israel.
Glass
G A
GA
D000975:Antioxidants / Q000494:pharmacology; D002570:Ceruloplasmin / Q000494:pharmacology*; D003300:Copper / Q000494:pharmacology*; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism* / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D016296:Mutagenesis / Q000187:drug effects*; D009152:Mutagenicity Tests / Q000379:methods; D009153:Mutagens / Q000494:pharmacology; D010084:Oxidation-Reduction; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D013438:Sulfhydryl Compounds / Q000494:pharmacology / Q000502:physiology; D005723:gamma-Glutamyltransferase / Q000187:drug effects / Q000235:genetics*
D000975:Antioxidants; D009153:Mutagens; D013438:Sulfhydryl Compounds; D003300:Copper; D006861:Hydrogen Peroxide; D002570:Ceruloplasmin; D005723:gamma-Glutamyltransferase; D005978:Glutathione