Magnetic resonance studies of fredericamycin A: evidence for oxygen-dependent free-radical formation

Hilton, Bruce D.; Misra, Renuka; Zweíer, Jay L.

doi:10.1021/bi00367a028

Cited by 34 publications

(28 citation statements)

References 12 publications

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“…3, no signal could be detected for any ofthese radicals in control nonphotosensitized skin (spectrum A), whereas the spectrum from DHE-treated skin (spectrum B) showed a number of signals consisting of two major components. One component with the coupling constants AN = 14.4 G and AH = 1 1.4 G was suggestive of DMPO-trapped O2 and the other component, a quartet (1:2:2:1) with the coupling constants AN = AH = 14.9 G was suggestive of DMPO-trapped OH (27)(28)(29). The spectra were further resolved in the presence of SOD and catalase.…”

Section: Resultsmentioning

confidence: 99%

“…This conclusion is also strengthened by our data showing that *°2 and OH were present in the skin of DHE-photosensitized mice as revealed by ESR spectral measurement of DMPO adducts of these radicals. The DMPO-O2 adduct is known to be decomposed forming DMPO-OH adduct (27,46). Thus, the presence of a DMPO-OH signal does not necessarily imply the generation of OH in the system.…”

Section: Discussionmentioning

confidence: 99%

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A novel mechanism for the generation of superoxide anions in hematoporphyrin derivative-mediated cutaneous photosensitization. Activation of the xanthine oxidase pathway.

Athar¹,

Elmets²,

Bickers³

et al. 1989

J. Clin. Invest.

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Prior studies, both in vitro and in vivo, have suggested that cutaneous porphyrin photosensitization requires the generation of superoxide anion 2O-) and various other reactive oxygen metabolites. No unifying concept has emerged, however, that unequivocally demonstrates the source of generation of these species. Since xanthine oxidase is known to generate *02 in reperfused ischemic tissue and in certain inflammatory disorders, we attempted to assess its role in porphyrin photosensitization. C3H mice were rendered photosensitive by the intraperitoneal administration of dihematoporphyrin ether (DHE) (5 mg/kg) followed by irradiation with visible light. Murine ear swelling was used as a marker of the acute photosensitization response and involvement of oxygen radicals was evaluated using electron spin resonance (ESR) spectroscopy. The administration of allopurinol, a potent inhibitor of xanthine oxidase, afforded 90% protection against DHE-mediated acute photosensitivity in vivo. Furthermore, xanthine oxidase activity was twofold higher in the skin of photosensitized mice than in unirradiated animals. ESR spectra of 5,5-dimethyl-1-pyrroline N-oxide-trapped radicals from the skin of photosensitized mice verified the presence of O2 and 'OH, while neither of these species was detected in the skin of control mice or mice receiving allopurinol. The administration of a soybean trypsin inhibitor or verapamil before irradiation also partially blocked the photosensitivity response, suggesting that calcium-dependent proteases play a role in the activation of xanthine oxidase in this photodynamic process. These data provide in vivo evidence for the involvement of O0 in DHE-mediated cutaneous photosensitization and suggest that these radicals are generated through the activation of the xanthine oxidase pathway. The administration of allopurinol and calcium channel blockers may thus offer new approaches for the treatment of cutaneous porphyrin photosensitization.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A novel mechanism for the generation of superoxide anions in hematoporphyrin derivative-mediated cutaneous photosensitization. Activation of the xanthine oxidase pathway.

Athar¹,

Elmets²,

Bickers³

et al. 1989

J. Clin. Invest.

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show abstract

“…EPR spectra were recorded with a VARIAN E-9 spectrometer operating at X-band, as described previously.21 Atomic absorption spectroscopy was performed with a Perkin-Elmer 5000 spectrophotometer. 22 Experimental protocol. After a 20 min equilibration period, baseline functional variables and two 5 min NMR spectra were recorded.…”

Section: Methodsmentioning

confidence: 99%

Improvement of postischemic myocardial function and metabolism induced by administration of deferoxamine at the time of reflow: the role of iron in the pathogenesis of reperfusion injury.

et al. 1987

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“…It (10). Quantitation of the free radical signals was performed by comparing the double integral of the observed signal to that of a known concentration of the TEMPO free radical in aqueous solution as described (4).…”

mentioning

confidence: 99%

Measurement of endothelial cell free radical generation: evidence for a central mechanism of free radical injury in postischemic tissues.

Zweíer

Kuppusamy

Lutty

1988

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

532

236

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Oxygen free radicals have been demonstrated to be important mediators of postischemic reperfusion injury in a broad variety of tissues; however, the cellular source of free radical generation is still unknown. In this study, electron paramagnetic resonance measurements with the spin trap 5,5'-dimethyl-1-pyrroline-N-oxide (DMPO) demonstrate that bovine endothelial cells subjected to anoxia and reoxygenation become potent generators of superoxide and hydroxyl free radicals. A prominent DMPO-OH signal aN = aH = 14.9 G is observed on reoxygenation after 45 min of anoxic incubation. Quantitatiye measurements of this free radical generation and the time course of radical generation are performed. Both superoxide dismutase and catalase totally abolish this radical signal, suggesting that O2 is sequentially reduced from 0 -to H202 to OHS. Addition of ethanol resulted in trapping of the ethQxy radical, further confirming the generation of OH-. Endothelial radical generation was shown to cause cell death, as evidenced by trypan blue uptake. Radical generation was partially inhibited and partially scavenged by the xanthine oxidase inhibitor allopurinol. Marked inhibition of radical generation was observed with the potent xanthine oxidase inhibitor oxypurinol. These studies 'demonstrate that endothelial cells subjected to anoxia and reoxygenation, conditions observed in ischemic and reperfused tissues, generate a burst of superoxide-derived hydroxyl free radicals that in turn cause cell injury and cell death. Most of this free radical generation appears to be from the enzyme xanthine oxidase. Thus, endothelial cell free radical generation may be a central mechanism of cellular injury in postischemic tissues.Over the past decade, increasing evidence has accumulated suggesting that reactive oxygen free radicals are generated in cells and tissues and are important mediators of a variety of important pathologic processes. Oxygen free radicals have been proposed to mediate postischemic reperfusion damage in a variety of tissues, including the heart, lung, kidney, gastrointestinal tract, and brain (1). In all of these tissues, it has been shown that intravascular administration of free radical scavenging enzymes or drugs can prevent reperfusion injury and enhance postischemic functional recovery. Thus, these studies have provided indirect evidence for free radical generation in a wide variety of organs. Free radical generation in postischemic tissues has been measured with electron paramagnetic resonance (EPR) techniques (2). Both direct and spin-trapping EPR techniques have demonstrated that there is a burst of oxygen free radical generation after postischemic reperfusion of the heart (2-7).While there is a compelling body of literature suggesting that oxygen free radicals are generated in postischemic tissues, the mechanism of this free radical generation is still poorly understood. It MATERIALS AND METHODSFetal bovine aortic endothelial cells were isolated essentially as described (8) except that 0.1% (wt/vol) tryps...

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Magnetic resonance studies of fredericamycin A: evidence for oxygen-dependent free-radical formation

Cited by 34 publications

References 12 publications

A novel mechanism for the generation of superoxide anions in hematoporphyrin derivative-mediated cutaneous photosensitization. Activation of the xanthine oxidase pathway.

A novel mechanism for the generation of superoxide anions in hematoporphyrin derivative-mediated cutaneous photosensitization. Activation of the xanthine oxidase pathway.

Improvement of postischemic myocardial function and metabolism induced by administration of deferoxamine at the time of reflow: the role of iron in the pathogenesis of reperfusion injury.

Measurement of endothelial cell free radical generation: evidence for a central mechanism of free radical injury in postischemic tissues.

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