Nitric oxide production in SJL mice bearing the RcsX lymphoma: a model for in vivo toxicological evaluation of NO.

Gal, Aharon; Tamir, Snait; Tannenbaum, Steven R.; Wogan, Gerald N.

doi:10.1073/pnas.93.21.11499

Cited by 32 publications

(26 citation statements)

References 34 publications

(20 reference statements)

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“…Results from our study clearly demonstrate, for the first time, enhanced formation of εdA and εdC in spleen DNA of SJL mice in association with NO overproduction. As previously reported (15,16), after injection of RcsX cells, iNOS expression in macrophages of spleen and lymph nodes was induced, 2083 resulting in a 50-fold increase in NO production over 14 days. Etheno adducts have been shown to be formed as a result of induced oxidative stress and lipid peroxidation (13,14,25).…”

Section: Discussionsupporting

confidence: 58%

“…Injection of RcsX cells into SJL mice has previously been shown to cause an inflammatory reaction in spleen and lymph nodes, susequently leading to an overproduction of NO that was detected by elevated nitrate excretion in urine (15,16). Further, immunohistochemical analyses revealed the induction of iNOS expression in certain subsets of cells within the spleen (19).…”

Section: Discussionmentioning

confidence: 99%

“…When superantigen-bearing RcsX cells were injected into SJL mice, iNOS expression in macrophages of spleen and lymph nodes was induced, resulting in a 50-fold increase in NO production over 14 days (15,16). Levels of 3-nitrotyrosine, a marker formed specifically from ONOO -under physiological conditions (17,18), was elevated in specific subsets of splenic cells of SJL mice under these conditions (19).…”

Section: Introductionmentioning

confidence: 99%

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Etheno adducts in spleen DNA of SJL mice stimulated to overproduce nitric oxide

Nair

Gal²,

Tamir³

et al. 1998

Carcinogenesis

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In order to investigate specific DNA damage caused by nitric oxide (NO) induced lipid peroxidation, levels of promutagenic etheno adducts 1,N 6 -ethenodeoxyadenosine (εdA) and 3,N 4 -ethenodeoxycytidine (εdC) were measured in spleen DNA of SJL mice induced to produce high levels of NO by injection of RcsX (pre-B-cell lymphoma) cells. εdA and εdC levels were quantified by an ultrasensitive immunoaffinity-32 P-post-labeling method. Spleen DNA of control mice (n ⍧ 5) had background levels of 9.2 ⍨ 5.4 εdA adducts per 10 9 dA and 13.1 ⍨ 5.7 εdC adducts per 10 9 dC. In RcsX cell-injected mice (n ⍧ 7), levels of these adducts were elevated~6-fold, i.e. 53.9 ⍨ 39.4 εdA per 10 9 dA and 83.5 ⍨ 57.8 εdC per 10 9 dC (P < 0.05). Mice injected with RcsX cells and also treated with N G -methyl-L-arginine (NMA), an inhibitor of inducible nitric oxide synthase (n ⍧ 6), had significantly reduced levels (P < 0.05) of both εdA and εdC (13.5 ⍨ 5.7 εdA per 10 9 dA and 28.2 ⍨ 15.7 εdC per 10 9 dC). These findings constitute the first available evidence of formation of etheno adducts associated with NO overproduction in vivo. The adducts were presumably formed from lipid peroxidation products such as trans-4-hydroxy-2-nonenal (HNE), generated via oxidation of lipids by peroxynitrite. The results suggest that etheno-DNA adducts, among other types of damage, may contribute to the etiology of cancers associated with chronic infection/inflammation in which NO is overproduced.

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Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Etheno adducts in spleen DNA of SJL mice stimulated to overproduce nitric oxide

Nair

Gal²,

Tamir³

et al. 1998

Carcinogenesis

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“…21 Cytotoxic effects of this gaseous radical on bacteria and tumor cells have been reported for many years. [22][23][24] Previous studies 25,26 have revealed that depletion of cellular GSH reduces the viability of cells exposed to NO.…”

Section: Discussionmentioning

confidence: 99%

Role of glutathione in nitric oxide-dependent regulation of energy metabolism in rat hepatoma cells

et al. 1998

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Previous studies in this laboratory revealed that nitric oxide (NO) reversibly inhibits the respiration of isolated mitochondria and ascites hepatoma (AH-130) cells by an oxygen concentration-dependent mechanism. The inhibitory effect of NO on the respiration of AH-130 cells was enhanced by treating with digitonin that selectively permeabilized plasma membranes and released cytosolic lowmolecular-weight compounds. Reduced glutathione (GSH) is the most abundant cytosolic thiol that easily reacts with NO. To elucidate the mechanism by which digitonin enhanced the inhibitory action of NO, the effect of GSH and related thiols was studied with AH-130 cells and their mitochondria. The inhibitory effect of NO on the respiration of digitonin-treated cells was suppressed by either GSH, L-cysteine, or N-acetylcysteine, but not by oxidized glutathione. The inhibitory effect of NO on the respiration of their mitochondria was also decreased by GSH. In contrast, the inhibitory effect of NO was markedly enhanced with AH-130 cells obtained from animals that were pretreated with L-buthionine sulfoximine (BSO), a specific inhibitor for GSH synthesis. Kinetic analysis revealed that NO dose-dependently decreased GSH levels in AH-130 cells with concomitant generation of S-nitrosothiols. Although S-nitrosoglutathione (GSNO), a slow releaser of NO, also inhibited the respiration of tumor cell mitochondria, its effect was significantly lower than that of NO. These results suggest that cellular GSH might play pivotal roles in the regulation of energy metabolism in hepatoma cells by modulating free forms of NO. (HEPATOLOGY 1998;27:422-426.)Nitric oxide (NO) interacts with various molecules, such as hemeproteins and nonhemeproteins, thereby acting as a multifunctional molecule. Through the modification of such proteins, NO reversibly inhibits the respiration of mitochondria. [1][2][3][4] Previous studies in this laboratory 5 revealed that NO reversibly binds to cytochrome c oxidase and inhibits the respiration of tumor cells. Because NO also reacts with molecular oxygen (k ϭ 6 ϫ 10 6 mol/L Ϫ2 s Ϫ1 ), mitochondrial respiration was inhibited by this gaseous radical more strongly at low oxygen tensions than at its high concentrations. 3,5 Furthermore, the inhibitory effect of NO is enhanced by selectively permeabilizing plasma membranes of tumor cells by digitonin. 5 These observations suggested the presence of some cytosolic molecule(s) that suppressed the effect of NO on mitochondrial respiration. Because NO forms nitrosoadducts with various thiols, such as reduced glutathione (GSH) and cysteine-containing proteins, 6 these thiol compounds might decrease the levels of free forms of NO, thereby affecting its fate and biological activity. Among various thiols in cells, GSH is a naturally occurring major thiol. Preliminary experiments in this laboratory revealed that permeabilization of plasma membrane by digitonin released cytosolic GSH and decreased cellular levels of it. The inhibitory effect of NO on the respiration of isolated mitochondr...

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“…To assess in vivo toxicological responses to excess NO ⅐ production in intact animals, an experimental model utilizing the SJL mouse was developed (10,11). In this model, mice were injected with superantigen-bearing RcsX (pre-B-cell lymphoma) cells.…”

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confidence: 99%

Mutagenesis associated with nitric oxide production in transgenic SJL mice

Gal

Wogan

1996

Proc. Natl. Acad. Sci. U.S.A.

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We recently reported development of an experimental model for the study of nitric oxide (NO ⅐ ) toxicology in vivo. SJL mice were injected with superantigen-bearing RcsX (pre-B-cell lymphoma) cells, which migrated to the spleen and lymph nodes, where their rapid growth induced activation of macrophages to produce large amounts of NO ⅐ over a period of several weeks. In the experiments described here, we used this model to investigate mutagenesis in splenocytes exposed to NO ⅐ during RcsX cell growth. Transgenic mice were produced by crossbreeding animals of the pUR288 transgenic C57BL͞6 and SJL strains. RcsX cells were injected into F 1 mice and NO ⅐ production was confirmed by quantification of urinary nitrate, the ultimate metabolite of NO ⅐ . Mutant frequency in the lacZ gene of the pUR288 plasmid was determined in DNA isolated from spleen (target) and kidney (nontarget) tissues. A significant elevation in mutant frequency was found in the spleen, but not in the kidney, of tumor-bearing mice. Furthermore, increases in mutant frequency in the spleen as well as NO ⅐ production were abrogated by administration of N-methylarginine, a NO ⅐ inhibitor, to mice following injection of RcsX cells. These results indicate that NO ⅐ had mutagenic activity in RcsX tumor-bearing mice and thus support a possible role for its involvement in the carcinogenic process.

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Nitric oxide production in SJL mice bearing the RcsX lymphoma: a model for in vivo toxicological evaluation of NO.

Cited by 32 publications

References 34 publications

Etheno adducts in spleen DNA of SJL mice stimulated to overproduce nitric oxide

Etheno adducts in spleen DNA of SJL mice stimulated to overproduce nitric oxide

Role of glutathione in nitric oxide-dependent regulation of energy metabolism in rat hepatoma cells

Mutagenesis associated with nitric oxide production in transgenic SJL mice

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