Alterations in the Binding of [Cl(NH3)5RuIII]2+ to DNA by Glutathione: Reduction, Autoxidation, Coordination, and Decomposition
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- 作者：Dominic R. Frasca and M. J. Clarke
- 刊名：Journal of the American Chemical Society
- 出版年：1999
- 出版时间：September 22, 1999
- 年：1999
- 卷：121
- 期：37
- 页码：8523 - 8532
- 全文大小：239K
- 年卷期：v.121,no.37(September 22, 1999)
- ISSN：1520-5126
文摘
The autoxidation of glutathione (GSH) is catalyzed by [Cl(NH3)5RuIII]2+ yielding only [OH(NH3)5RuIII]2+ and GSSG according to the rate law d[GSSG]/dt = k[Ru][GSH], where k = 3 M-1 s-1. The anaerobicreaction of GSH with [Cl(NH3)5RuIII]2+ yields first [OH(NH3)5RuIII]2+ and then [GS(NH3)5RuIII]+ at neutralpH, both through redox catalysis. The reaction appears to proceed through reduction of RuIII by GSH to give[H2O(NH3)5RuII]2+, followed by coordination to produce [GSH(NH3)5RuII]2+ and then oxidation of the latterion by [OH(NH3)5RuIII]2+ or GSSG to yield [GS(NH3)5RuIII]+. [GS(NH3)5RuIII]+ is also produced by the reactionof GSH with [(NH3)6Ru]3+ or [py(NH3)5Ru]3+. Glutathione reduces [OH(NH3)5RuIII]2+ through a pre-equilibriummechanism according to the following rate law: d[RuII]/dt = k[RuIII][GSH]/(Ki + [GSH]), where Ki = 2.0 ×10-3 M-1 and k = 2.3 × 10-3 s-1. The reduction potential of [(GS)(NH3)5RuIII,] is pH-dependent accordingto the Nernstian equation: E = E
mages/entities/deg.gif"> - 0.59log {Ka/([H+] + Ka)}, where Emages/entities/deg.gif"> = -440 mV, pKa = 7.1. While[GS(NH3)5RuIII] is stable for extended periods under inert atmosphere, it changes in air, eventually yielding[HO(NH3)5RuIII] among other products at high pH with kobs (s-1) = (k1Ka + k2[H+])/([H+] + Ka), where k1= 9 × 10-6 s-1, k2 = 1.2 × 10-4 s-1 M-1, and pKa = 12. At [GSH]/[RuIII] mages/entities/le.gif"> 1, the coordination of [Cl(NH3)5RuIII]2+ to DNA is facilitated by GSH reduction to the more substitution-labile [H2O(NH3)5RuII]2+.However, at [GSH]/[RuIII] mages/entities/ge.gif"> 1, guanine binding on DNA is inhibited by GSH, which coordinates RuII andfacilitates oxidation back to RuIII because of the low Emages/entities/deg.gif"> of [GS(NH3)5RuIII]+. Consistent with this is the increasedtoxicity of [Cl(NH3)5RuIII]2+ to Jurkat T-cells, when GSH levels are suppressed. High [GSH]/[Ru] alters theDNA binding of [H2O(NH3)5RuII]2+ to essentially eliminate G7 coordination and lower C4 binding, but leavingA6 binding relatively unaffected, which may have implications for the mechanism of ruthenium antitumoragents.