Farias-Eisner R, Chaudhuri G, Aeberhard E, Fukuto J M
Department of Obstetrics-Gynecology, University of California at Los Angeles School of Medicine, 90095-1735, USA.
J Biol Chem. 1996 Mar 15;271(11):6144-51. doi: 10.1074/jbc.271.11.6144.
The mechanism of cytotoxicity of the NO donor 3-morpholino-sydnonimine toward a human ovarian cancer cell line (OVCAR) was examined. It was found that the NO-mediated loss of cell viability was dependent on both NO and hydrogen peroxide (H2O2). Somewhat surprisingly, superoxide (O2) and its reaction product with NO, peroxynitrite (-OONO), did not appear to be di- rectly involved in the observed NO-mediated cytotoxicity against this cancer cell line. The toxicity of NO/H2O2 may be due to the production of a potent oxidant formed via a trace metal-, H202-, and NO-dependent process. Because the combination of NO and H2O2 was found to be particularly cytotoxic, the effect of NO on cellular defense mechanisms involving H2O2 degradation was investigated. It was found that NO was able to inhibit catalase activity but had no effect on the activity of the glutathione peroxidase (GSHPx)-glutathione reductase system. It might therefore be expected that cells that utilize primarily the GSHPx-glutathione reductase system for degrading H2O2 would be somewhat resistant to the cytotoxic effects of NO. Consistent with this idea, it was found that ebselen, a compound with GSHPx-like activity, was able to protect cells against NO toxicity. Also, lowering endogenous GSHPx activity via selenium depletion resulted in an increased susceptibility of the target cells to NO-mediated toxicity. Thus, a possible NO/H2O2/metal-mediated mechanism for cellular toxicity is presented as well as a possible explanation for cell resistance/susceptibility to this NO-initiated process.
研究了一氧化氮供体3-吗啉代西多胺对人卵巢癌细胞系（OVCAR）的细胞毒性机制。发现一氧化氮介导的细胞活力丧失既依赖于一氧化氮，也依赖于过氧化氢（H2O2）。有点令人惊讶的是，超氧化物（O2）及其与一氧化氮的反应产物过氧亚硝酸盐（-OONO）似乎并未直接参与观察到的一氧化氮对该癌细胞系的细胞毒性作用。一氧化氮/过氧化氢的毒性可能是由于通过痕量金属、H2O2和一氧化氮依赖性过程形成的一种强效氧化剂的产生。由于发现一氧化氮和过氧化氢的组合具有特别的细胞毒性，因此研究了一氧化氮对涉及H2O2降解的细胞防御机制的影响。发现一氧化氮能够抑制过氧化氢酶的活性，但对谷胱甘肽过氧化物酶（GSHPx）-谷胱甘肽还原酶系统的活性没有影响。因此，可以预期主要利用GSHPx-谷胱甘肽还原酶系统来降解H2O2的细胞对一氧化氮的细胞毒性作用会有一定的抗性。与此观点一致，发现具有GSHPx样活性的化合物依布硒仑能够保护细胞免受一氧化氮的毒性作用。此外，通过耗尽硒来降低内源性GSHPx活性会导致靶细胞对一氧化氮介导的毒性的敏感性增加。因此，提出了一种可能的一氧化氮/过氧化氢/金属介导的细胞毒性机制以及对细胞对这种一氧化氮引发过程的抗性/敏感性的一种可能解释。
