PURPOSE: We have recently reported that degradation of FK409 with generation of NO is spontaneous and is accelerated in the presence of sulfhydryl-bearing compounds, such as L-cysteine (Cys) and glutathione (GSH). The purpose of the present study is to investigate the NO-releasing pathway of FK409 in the presence of sulfhydryl-bearing compounds. METHODS: The degradation process of FK409 in the presence of Cys or GSH was investigated by means of 1H-nuclear magnetic resonance (NMR) spectroscopy and high-performance liquid chromatography (HPLC). RESULTS: The degradation of FK409 in the presence of Cys was dependent on concentration of Cys, and showed pH-dependency, accelerating with an increase in pH. The 1H-NMR spectra of FK409 with Cys suggested that time-dependent elimination of the hydrogen atom at the alpha-position of the nitro moiety (5-position) was accelerated by Cys in weakly alkaline solution. Cys and GSH were transformed readily, concomitant with FK409 degradation, to give their oxidized forms and probably S-nitrosothiols. CONCLUSION: The effect of sulfhydryl-bearing compounds on FK409 degradation is due to the acceleration of deprotonation of the hydrogen atom at the 5-position by thiolate anion as well as hydroxyl ion. Sulfhydryl-bearing compounds reacted with the released NO resulting in formation of disulfides via intermediate S-nitrosothiols.
PURPOSE: We have recently reported that degradation of FK409 with generation of NO is spontaneous and is accelerated in the presence of sulfhydryl-bearing compounds, such as L-cysteine (Cys) and glutathione (GSH). The purpose of the present study is to investigate the NO-releasing pathway of FK409 in the presence of sulfhydryl-bearing compounds. METHODS: The degradation process of FK409 in the presence of Cys or GSH was investigated by means of 1H-nuclear magnetic resonance (NMR) spectroscopy and high-performance liquid chromatography (HPLC). RESULTS: The degradation of FK409 in the presence of Cys was dependent on concentration of Cys, and showed pH-dependency, accelerating with an increase in pH. The 1H-NMR spectra of FK409 with Cys suggested that time-dependent elimination of the hydrogen atom at the alpha-position of the nitro moiety (5-position) was accelerated by Cys in weakly alkaline solution. Cys and GSH were transformed readily, concomitant with FK409 degradation, to give their oxidized forms and probably S-nitrosothiols. CONCLUSION: The effect of sulfhydryl-bearing compounds on FK409 degradation is due to the acceleration of deprotonation of the hydrogen atom at the 5-position by thiolate anion as well as hydroxyl ion. Sulfhydryl-bearing compounds reacted with the released NO resulting in formation of disulfides via intermediate S-nitrosothiols.
Authors: L J Ignarro; H Lippton; J C Edwards; W H Baricos; A L Hyman; P J Kadowitz; C A Gruetter Journal: J Pharmacol Exp Ther Date: 1981-09 Impact factor: 4.030
Authors: M Hino; M Iwami; M Okamoto; K Yoshida; H Haruta; M Okuhara; J Hosoda; M Kohsaka; H Aoki; H Imanaka Journal: J Antibiot (Tokyo) Date: 1989-11 Impact factor: 2.649
Authors: J S Stamler; D I Simon; J A Osborne; M E Mullins; O Jaraki; T Michel; D J Singel; J Loscalzo Journal: Proc Natl Acad Sci U S A Date: 1992-01-01 Impact factor: 11.205