Nitrosation, Nitration, and Autoxidation of the Selective Estrogen Receptor Modulator Raloxifene by Nitric Oxide, Peroxynitrite, and Reactive Nitrogen/Oxygen Species
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- 作者：Violeta Toader ; Xudong Xu ; Adrian Nicolescu ; Linning Yu ; Judy L. Bolton ; and Gregory R. J. Thatcher
- 刊名：Chemical Research in Toxicology
- 出版年：2003
- 出版时间：October 2003
- 年：2003
- 卷：16
- 期：10
- 页码：1264 - 1276
- 全文大小：203K
- 年卷期：v.16,no.10(October 2003)
- ISSN：1520-5010
文摘
The regulation of estrogenic and antiestrogenic effects by selective estrogen receptormodulators (SERMs) provides the basis for use in long-term therapy in cancer chemopreventionand postmenopausal osteoporosis. However, the evidence for carcinogenic properties withinthis class requires study of potential pathways of toxicity. There is strong evidence for theelevation of cellular levels of NO in tissue treated with SERMs, including the benzothiophenederivative, raloxifene, in part via up-regulation of nitric oxide synthases. Therefore, thereactions of 17
-estradiol (E2), raloxifene, and an isomer with NO, peroxynitrite, and reactivenitrogen/oxygen species (RNOS) generated from NO2-/H2O2 systems were examined. Peroxynitrite from bolus injection or slow release from higher concentrations of 3-morpholinosydnonimine (SIN-1) reacted with the benzothiophenes and E2 to give aromatic ring nitration,whereas peroxynitrite, produced from the slow decomposition of lower concentrations of SIN-1, was relatively unreactive toward E2 and yielded oxidation and nitrosation products withraloxifene and its isomer. The oxidation and nitrosation products formed were characterizedas a dimer and quinone oxime derivative. Interestingly, the reaction of the benzothiopheneswith NO in aerobic solution efficiently generated the same oxidation products. Stable quinoneoximes are not unprecedented but have not been previously reported as products of RNOS-mediated metabolism. The reaction of glutathione (GSH) with the quinone oxime gave bothGSH adducts from Michael addition and reduction to the corresponding o-aminophenol. Theready autoxidation of raloxifene, observed in the presence of NO, is the first such observationon the reactivity of SERMs and is potentially a general phenomenon of significance to SERMchemical toxicology.
-estradiol (E2), raloxifene, and an isomer with NO, peroxynitrite, and reactivenitrogen/oxygen species (RNOS) generated from NO2-/H2O2 systems were examined. Peroxynitrite from bolus injection or slow release from higher concentrations of 3-morpholinosydnonimine (SIN-1) reacted with the benzothiophenes and E2 to give aromatic ring nitration,whereas peroxynitrite, produced from the slow decomposition of lower concentrations of SIN-1, was relatively unreactive toward E2 and yielded oxidation and nitrosation products withraloxifene and its isomer. The oxidation and nitrosation products formed were characterizedas a dimer and quinone oxime derivative. Interestingly, the reaction of the benzothiopheneswith NO in aerobic solution efficiently generated the same oxidation products. Stable quinoneoximes are not unprecedented but have not been previously reported as products of RNOS-mediated metabolism. The reaction of glutathione (GSH) with the quinone oxime gave bothGSH adducts from Michael addition and reduction to the corresponding o-aminophenol. Theready autoxidation of raloxifene, observed in the presence of NO, is the first such observationon the reactivity of SERMs and is potentially a general phenomenon of significance to SERMchemical toxicology.