Nitroxides as Protectors Against Oxidative Stress

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Summary Nitroxides are proving to have broad utility in a number of disease processes and/or conditions that represent excessive oxidative stress. The fact that nitroxides exert activity over such a range of conditions speaks to the importance of free radical reactions in tissue. Likewise, it is becoming apparent that free radicals are important in normal molecular signaling pathways and related gene expression. We continue to search for the mechanism(s) of how long-term administration of Tempol (in the food or drinking water) results in dramatic weight reduction and a decrease in spontaneous tumor incidence in mice. Gene expression profile studies of selected tissues were conducted to obtain early gene expression changes by Tempol in mice prior to changes in weight (14 days) and later when animal weights were reduced by Tempol (60 days). The majority of gene changes (both up- and down-regulated) resulting from the Tempol diet occurred in the liver. Tempol diet up-regulated genes related to mitochondrial function and fatty acid and/or lipid synthesis. Glutathione metabolism genes and Nrf2 genes (which provide protection against free radicals) were up-regulated. We are currently evaluating the effect of Tempol on gene expression profiles in adipose tissue, in particular if proteins modulation can be observed from genes either up- or down-regulated. Tempol administration to mice either in the diet or by gavage resulted in hundreds of urine metabolic products including numerous Tempol metabolites. Of particular interest were metabolites such as 2,8-dihydroxylquinoline and its glucuonide, which were elevated and metabolites such as panthothenic acid and isobutrylcarnitine which were significantly attenuated compared to control. Current studies are focusing on whether the presence of 2,8-dihydroxylquinoline is related to the gut microflora and how Tempol might be impacting the gut microflora. Further elevation of 2,8-dihydroxylquinoline may signal that Tempol treatment induces fatty acid beta-oxidation. Lastly, in a related project dealing with oxidative stress, we evaluated whether the presence of a tumor in a mouse alters urine metabolite profiles. A number of different urine and blood metabolites were found to be elevated in tumor-bearing mice including hexanoylglycine, nicotinamide 1-oxide, dimethylargine (biomarker for oxidative stress) and c-reactive protein (inflammatory biomarker). Further, mRNA analysis of liver indicated the induction of inflammatory cytokines, TNF, and TGF-beta and decrease in liver cytochromes P450. Elevated serum triglycerides were elevated suggesting liver dysfunction. Collectively, these findings suggest that tumor growth induces an inflammatory response resulting in liver dysfunction. Whether Tempol administration in mice could dampen this response and impact tumor growth is being studied currently.