Characterisation of the decomposition behaviour of S-nitrosoglutathione and a new class of analogues: S-Nitrosophytochelatins

King's College London, Pharmaceutical Sciences Division, 150 Stamford Street, London SE1 9NH, UK.
Nitric Oxide (Impact Factor: 3.52). 12/2008; 20(3):157-65. DOI: 10.1016/j.niox.2008.11.001
Source: PubMed


S-Nitrosoglutathione (GSNO) is one of the most abundant S-nitrosothiols present in the body, playing an important role in many important physiological functions. Depletion of GSNO in some pathophysiological conditions makes GSNO a potentially interesting therapeutic molecule. Phytochelatins are glutathione analogues with the following structure: (gamma-glutamyl-cysteine)(n)-glycine. S-Nitroso derivatives of phytochelatins (SNOPCs) carry a greater number of S-nitrosothiol groups per molecule than GSNO and might therefore be very useful as therapeutic agents. The aim of this study was to investigate the in vitro decomposition behaviour of SNOPCs under various physicochemical stress conditions and compare it to the decomposition behaviour of GSNO. SNOPCs were generally less stable than GSNO under all experimental conditions tested, which included exposure to light, variation of pH and temperature as well as exposure to different concentrations of exogenous free thiol in the form of reduced glutathione (GSH). Even under light exclusion at ambient temperature the SNOPCs retained only 40% of their intact SNO groups after a 48h incubation time compared to 90% for GSNO. SNOPCs were also shown to readily take part in transnitrosation reactions when incubated with free glutathione. These properties suggest that SNOPCs could be employed as an investigation tool or possibly as therapeutic agents.

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    • "Around 10% of intact GSNO remained in the nanocomposite particles after 15 days under the same conditions. As reported byHeikal et al. (2009), an increase in temperature led to a decrease in stability of GSNO and higher rates of decomposition. In our study, at 37 C, free GSNO decomposed more rapidly: 100% was degraded in 4 days. "
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    ABSTRACT: S-nitrosoglutathione (GSNO) is a nitric oxide (NO) donor with therapeutic potential for cardiovascular disease treatment. Chronic oral treatment with GSNO is limited by high drug sensitivity to the environment and limited oral bioavailability, requiring the development of delivery systems able to sustain NO release. The present work describes new platforms based on polymer nanocomposite particles for the delivery of GSNO. Five types of optimized nanocomposite particles have been developed (three based on chitosan, two based on alginate sodium). Those nanocomposite particles encapsulate GSNO with high efficiency from 64% to 70% and an average size of 13 to 61μm compatible with oral delivery. Sustained release of GSNO in vitro was achieved. Indeed, chitosan nanocomposites discharged their payload within 24h; whereas alginate nanocomposites released GSNO more slowly (10% of GSNO was still remaining in the dosage form after 24h). Their cytocompatibility towards intestinal Caco-2 cells (MTT assay) was acceptable (IC50: 6.07±0.07mg/mL to 9.46±0.08mg/mL), demonstrating their suitability as oral delivery systems for GSNO. These delivery systems presented efficient GSNO loading and sustained release as well as cytocompatibility, showing their promise as a means of improving the oral bioavailability of GSNO and as a potential new treatment. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Aug 2015 · International Journal of Pharmaceutics
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    • "In this procedure GSH is quantitatively conjugated to 1-chloro-2,4-dinitrobenzene (CDNB) by glutathione-Stransferase (GST) followed by HPLC analysis of the adduct produced. The advantage of this procedure over others is that GSNO is not exposed to an environment with pH greater than 7. GSNO is known to be more labile at alkaline than at neutral or acidic pH values [44] [45]. For this purpose, N 2 -saturated samples containing 100 μM DETAPAC, 100 μM neocuproine, 6 U of GST /mL and 40 mM phosphate buffer (pH 7.4) were prepared. "
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    ABSTRACT: Quinones are one of the largest classes of antitumor agents approved for clinical use, and several antitumor quinones are in various stages of clinical and preclinical development. Many of these are metabolites of, or are, environmental toxins. Because of their chemical structure they are known to enhance electron transfer processes such as ascorbate oxidation and NO reduction. The paraquinones 2,6-dimethyl-1,4-benzoquinone (DMBQ), 1,4-benzoquinone, methyl-1,4-benzoquinone, 2,6-dimethoxy-1,4-benzoquinone, 2-hydroxymethyl-6-methoxy-1,4-benzoquinone, trimethyl-1,4-benzoquinone, tetramethyl-1,4-benzoquinone, and 2,3-dimethoxy-5-methyl-1,4-benzoquinone; the paranaphthoquinones 1,4-naphthoquinone, menadione, 1,4-naphthoquinone-2-sulfonate, 2-ethylsulfanyl-3-methyl-1,4-naphthoquinone and juglone; and phenanthraquinone (PHQ) all enhance the anaerobic rate of ascorbate reduction of GSNO to produce NO and GSH. Rates of this reaction were much larger for p-benzoquinones and PHQ than for p-naphthoquinone derivatives with similar one-electron redox potentials. The quinone DMBQ also enhances the rate of NO production from S-nitrosylated bovine serum albumin upon ascorbate reduction. Density functional theory calculations suggest that stronger interactions between p-benzo- or phenanthrasemiquinones and GSNO than between p-naphthosemiquinones and GSNO are the major causes of these differences. Thus, quinones, and especially p-quinones and PHQ, could act as enhancers of NO release from GSNO in biomedical systems in the presence of ascorbate. Because quinones are exogenous toxins that could enter the human body via a chemotherapeutic application or as an environmental contaminant, they could boost the release of NO from S-nitrosothiol storages in the body in the presence of ascorbate and thus enhance the responses elicited by a sudden increase in NO levels.
    Full-text · Article · Nov 2010 · Free Radical Biology and Medicine
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    • "S-Nitrosothiols (RSNO) are generally believed as the bio reservoir for nitric oxide (NO) in a biological system [1] and hence their various ways of decomposition are very relevant [2] [3] [4] [5] [6] [7]. The bond dissociation energy for S–N bond is between 20 and 32 kcal mol −1 [8] [9]. "
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    ABSTRACT: Photochemical release of nitric oxide (NO) from the S-nitroso derivatives of glutathione, L-cysteine, N-acetyl-L-cysteine, L-cysteinemethylester, D,L-penicillamine, N-acetyl-D,L-penicillamine, and N-acetylcysteamine has been investigated at neutral and acidic pH. The release of NO from RSNO is one of the key reactions that could be utilized in photodynamic therapy. The UV-VIS and HPLC analyses have shown that under argon saturated conditions, disulfide (RSSR) is the major product of UV as well as sunlight induced decomposition. While in aerated conditions, nitirite—the end product of the oxidation of NO—was also observed along with disulfide. The formation of thiyl radical as the intermediate was reconfirmed by laser flash photolysis. The initial rate of formation of NO was on the order of 10−5 dm3 mol−1 s−1. The quantum yields of these reactions were in the range of 0.2–0.8. The high quantum yields observed in the photo induced release of NO from RSNO using both UV and sunlight demonstrate the potential application of these reactions in photodynamic therapy.
    Full-text · Article · Jan 2009 · Advances in Physical Chemistry
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