Prodrug Approach for Increasing Cellular Glutathione Levels 英文参考文献.docVIP

Molecules 2010, 15, 1242-1264; doi:10.3390/moleculeOPEN ACCESS molecules ISSN 1420-3049 /journal/molecules Review Prodrug Approach for Increasing Cellular Glutathione Levels Ivana Cacciatore, Catia Cornacchia, Francesco Pinnen, Adriano Mollica and Antonio Di Stefano * Department of Drug Sciences, School of Pharmacy, “G. dAnnunzio” University, Via dei Vestini 31, 66100 Chieti, Italy * Author to whom correspondence should be addressed; E-Mail: adistefano@unich.it; Tel.: +39-871-3554708; Fax: +39-871-3554706. Received: 8 February 2010; in revised form: 2 March 2010 / Accepted: 3 March 2010 / Published: 3 March 2010 Abstract: Reduced glutathione (GSH) is the most abundant non-protein thiol in mammalian cells and the preferred substrate for several enzymes in xenobiotic metabolism and antioxidant defense. It plays an important role in many cellular processes, such as cell differentiation, proliferation and apoptosis. GSH deficiency has been observed in aging and in a wide range of pathologies, including neurodegenerative disorders and cystic fibrosis (CF), as well as in several viral infections. Use of GSH as a therapeutic agent is limited because of its unfavorable biochemical and pharmacokinetic properties. Several reports have provided evidence for the use of GSH prodrugs able to replenish intracellular GSH levels. This review discusses different strategies for increasing GSH levels by supplying reversible bioconjugates able to cross the cellular membrane more easily than GSH and to provide a source of thiols for GSH synthesis. Keywords: glutathione; glutathione deficiency; glutathione prodrugs 1. Introduction Glutathione (γ-L-glutamyl-L-cysteinylglycine, GSH), a water-soluble endogenous tripeptide, is the most abundant thiol present in mammalian cells, with concentrations up to 10 mM [1]. The liver, one of the tissues with the highest content of this tripeptide, is the main tissue