Nitroxides, which are potent antioxidants, 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 disease 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. Further, nitroxide application (lead compound is Tempol) in the diet of mice has been found to prevent obesity. A number of studies are underway to elucidate the mechanism of obesity prevention. Tempol administration to mice either in the diet or by gavage resulted in hundreds of altered 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. The presence of 2,8-dihydroxylquinoline is related to the gut microflora, which prompted a study to determine if Tempol treatment would alter the gut microflora profile in mice. Tempol administration was found to significantly change the gut microflora composition, in particular the Firmicute/Bacteroidete ratio consistent with a lean phenotype. The change in this ratio resulted from Tempol-medicated reduction of Lactobacillus and bile salt hydrolase activity leading to an accumulation of tauro-beta- muricholic acid (T-beta-MCA). Elevated T-beta-MCA inhibits farnesoid (FXR) signaling thus impacting lipid and glucose metabolism, which may underlie the anti-obesity properties of Tempol. Tempol has been shown to protect against free radical mediated DNA damage for ionizing radiation and hydrogen peroxide. Additional studies have demonstrated protection of DNA damage from the reverse transcriptase inhibitor NRTI and zidovudine. Lastly, tumor growth in mice results in systemic oxidative stress as evidenced by DNA damage in a variety of organs. Tumor-bearing animals on a Tempol-containing diet exhibited significantly less DNA damage to organs.
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