title: S-allylmercapto-N-acetylcysteine up-regulates cellular glutathione and protects vascular endothelial cells from oxidative stress.
abstract: Oxidative stress and/or low cellular glutathione (GSH) levels are associated with the development and progression of numerous pathological conditions. Cells possess various antioxidant protection mechanisms, including GSH and phase II detoxifying enzymes. N-acetylcysteine (NAC) supplies cells with cysteine to increase GSH level but its efficacy is relatively low because of its limited tissue penetration. Allicin (diallyl thiosulfinate), a reactive sulfaorganic compound, increases cellular GSH and phase II detoxifying enzymes in vascular endothelial cells (EC). A novel compound was designed: S-allylmercapto-N-acetylcysteine (ASSNAC), a conjugate of S-allyl mercaptan (a component of allicin) and NAC. Both ASSNAC and NAC increased cellular GSH of ECs, reaching a maximum of up to four- and threefold increase after exposure for 24 or 6 h at a concentration of 0.2 or 1 mM, respectively. ASSNAC induced nuclear translocation of the activated transcription factor Nrf2 and expression of phase II detoxifying enzymes. EC exposure to tBuOOH resulted in 75% cytotoxicity, and pretreatment of cultures with 0.2 mM ASSNAC or 2mM NAC reduced cytotoxicity to 20 and 42%, respectively. In conclusion, ASSNAC is superior to NAC in protecting cells from oxidative stress because of its ability to up-regulate both GSH and the expression of phase II detoxifying enzymes.
authors.affiliation: Goldschleger Eye Research Institute, Tel Hashomer 52621, Israel.
authors.forename: Nira
authors.initials: N
authors.lastname: Izigov
authors.forename: Nahid
authors.initials: N
authors.lastname: Farzam
authors.forename: Naphtali
authors.initials: N
authors.lastname: Savion
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000494:pharmacology*; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D003545:Cysteine / Q000378:metabolism; D019610:Cytoprotection; D004220:Disulfides; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D050217:Metabolic Detoxication, Phase II; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D013441:Sulfinic Acids / Q000737:chemistry; D015533:Transcriptional Activation; D015854:Up-Regulation; D020122:tert-Butylhydroperoxide / Q000633:toxicity
chemical_list: D000975:Antioxidants; D004220:Disulfides; D051267:NF-E2-Related Factor 2; D013441:Sulfinic Acids; C006452:allicin; D020122:tert-Butylhydroperoxide; D005978:Glutathione; D003545:Cysteine; D000111:Acetylcysteine