Allopurinol: Discrimination of antioxidant from enzyme inhibitory activities

Klein, Andrew S.; Joh, Jae‐Won; Rangan, U.; Wang, Dajie; Bulkley, Gregory B.

doi:10.1016/0891-5849(96)00158-x

Cited by 46 publications

(31 citation statements)

References 9 publications

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“…Moreover, several reports have shown that allopurinol itself does not scavenge superoxide directly (39). We used allopurinol pretreatment, followed by formate and POBN administration, to reveal a possible role of this enzyme in radical formation.…”

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confidence: 99%

An in vivo ESR spin-trapping study: Free radical generation in rats from formate intoxication— role of the Fenton reaction

Dikalova

Kadiiska

Mason

2001

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

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Electron spin resonance spectroscopy has been used to study free radical generation in rats with acute sodium formate poisoning. The in vivo spin-trapping technique was used with ␣-(4-pyridyl-1-oxide)-N-t-butylnitrone (POBN), which reacts with free radical metabolites to form radical adducts, which were detected in the bile and urine samples from Fischer rats. The use of [ 13 C]-sodium formate and computer simulations of the spectra identified the 12-line spectrum as arising from the POBN͞carbon dioxide anion radical adduct. The identification of POBN͞ ⅐ CO 2 ؊ radical adduct provides direct electron spin resonance spectroscopy evidence for the formation of ⅐ CO 2 ؊ radicals during acute intoxication by sodium formate, suggesting a free radical metabolic pathway. To study the mechanism of free radical generation by formate, we tested several known inhibitors. Both allopurinol, an inhibitor of xanthine oxidase, and aminobenzotriazole, a cytochrome P450 inhibitor, decreased free radical formation from formate, which may imply a dependence on hydrogen peroxide. In accord with this hypothesis, the catalase inhibitor 3-aminotriazole caused a significant increase in free radical formation. The iron chelator Desferal decreased the formation of free radicals up to 2-fold. Presumably, iron plays a role in the mechanism of free radical generation by formate via the Fenton reaction. The detection of formate free radical metabolites generated in vivo and the key role of the Fenton reaction in this process may be important for understanding the pathogenesis of both formate and methanol intoxication.

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mentioning

confidence: 99%

An in vivo ESR spin-trapping study: Free radical generation in rats from formate intoxication— role of the Fenton reaction

Dikalova

Kadiiska

Mason

2001

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

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“…26,27 The relevance of this hypothesis was disputed based on the fact that the antioxidant capacity in plasma did not significantly increase after allopurinol doses of up to 100 mg/kg. 28,29 In vitro, allopurinol is not a potent inhibitor of lipid peroxidation. 29 Although it cannot be completely ruled out that allopurinol, oxypurinol, or the accumulating substrates xanthine or hypoxanthine may scavenge free radicals, the overall impact of this mechanism may be limited.…”

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confidence: 99%

“…28,29 In vitro, allopurinol is not a potent inhibitor of lipid peroxidation. 29 Although it cannot be completely ruled out that allopurinol, oxypurinol, or the accumulating substrates xanthine or hypoxanthine may scavenge free radicals, the overall impact of this mechanism may be limited. During coronary artery occlusion and reperfusion experiments in rabbits, allopurinol preserved the structural integrity of mitochondria in the absence of xanthine oxidase in this species.…”

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confidence: 99%

Xanthine oxidase-induced oxidant stress during hepatic ischemia-reperfusion: Are we coming full circle after 20 years?

Jaeschke

2002

Hepatology

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“…2E). Our group previously reported that DPI ϩ allopurinol shows additive effects in reducing the generation of reactive oxygen metabolites by XO-and NADPH oxidase-dependent pathways (14). The additive effects of DPI and allopurinol in preventing an LPS-induced increase in FasL protein levels (ϳ75%; Fig.…”

Section: Discussionmentioning

confidence: 92%

Lipopolysaccharides induced increases in Fas ligand expression by Kupffer cells via mechanisms dependent on reactive oxygen species

Uchikura

Wada

Hoshino

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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Fas-Fas ligand (FasL)-dependent pathways exert a suppressive effect on inflammatory responses in immune-privileged organs. FasL expression in hepatic Kupffer cells (KC) has been implicated in hepatic immunoregulation. In this study, modulation of FasL expression of KC by endogenous gut-derived bacterial LPS and the role of reactive oxygen species (ROS) as potential mediators of FasL expression in KC were investigated. LPS stimulation of KC resulted in upstream ROS generation and, subsequently, increased FasL expression and consequent Jurkat cell (Fas-positive) apoptosis. The NADPH oxidase and xanthine oxidase enzymatic pathways appear to be major sources of this upstream ROS generation. Increased FasL expression was blocked by antioxidants and by enzymatic blocking of ROS generation. Exogenous administration of H2O2stimulated KC FasL expression and subsequent Jurkat cell apoptosis. Intracellular endogenous ROS generation may therefore represent an important signal transduction pathway for FasL expression in KC.

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Allopurinol: Discrimination of antioxidant from enzyme inhibitory activities

Cited by 46 publications

References 9 publications

An in vivo ESR spin-trapping study: Free radical generation in rats from formate intoxication— role of the Fenton reaction

An in vivo ESR spin-trapping study: Free radical generation in rats from formate intoxication— role of the Fenton reaction

Xanthine oxidase-induced oxidant stress during hepatic ischemia-reperfusion: Are we coming full circle after 20 years?

Lipopolysaccharides induced increases in Fas ligand expression by Kupffer cells via mechanisms dependent on reactive oxygen species

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