Intracellular thiol concentration modulating inflammatory response: influence on the regulation of cell functions through cysteine prodrug approach.
Oxidative stress is defined as the consequence of overpowering of the immune system's reaction, which causes increased production of the reactive oxidative species (ROS) greater than the antioxidant protection. Tissue injury and oxidation of the circulating molecules may be the consequences. Moreover, the sulphur-containing amino acids (SAA) fate is perturbed during stress. The altered biochemical rules during inflammation weaken the anti-oxidant mechanism, and the extra-supply of SAA under inflammatory conditions can help to restore homeostasis. In brief, the main biochemical steps during inflammation are: The production of Cytokines, Acute Phase Protein, and Glutathione (GSH) pool are strongly modified during inflammation. The GSH participates in many important physiological processes controlling the homeostasis of the cells. A higher demand of Cysteine (Cys) supply causes difficulties in maintaining a constant GSH level. The role of GSH as a key regulator of thiol redox intracellular balance is established. This reveals that GSH is essential in regulating the cell's life cycle and that the reduction of intracellular GSH contributes to chronic inflammation. The fact that Cys availability is generally a limiting factor for the GSH synthesis stimulated the development of a pharmacologically useful Cys pro-drug. The simplest derivative is N-acetylcysteine (NAC), which appears to be the prototype of all Cys suppliers. Different approaches are presented here.
Santangelo
F
F
Pharma R&D, Zambon Group Spa, Via Lillo del Duca, 10, 20091 Bresso, Milano, Italy. francesco.santangelo@fastwebnet.it
D000111:Acetylcysteine / Q000494:pharmacology; D000209:Acute-Phase Proteins / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D003545:Cysteine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000378:metabolism* / Q000494:pharmacology; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology
D000209:Acute-Phase Proteins; D016207:Cytokines; D011355:Prodrugs; D013438:Sulfhydryl Compounds; D013844:Thiazoles; D005978:Glutathione; D003545:Cysteine; D000111:Acetylcysteine