The role of superoxide radicals in lactoperoxidase-catalysed H2O2 — metabolism and in irreversible enzyme inactivation

Jenzer, Herbert; Köhler, H.

doi:10.1016/s0006-291x(86)80117-6

Cited by 26 publications

(31 citation statements)

References 4 publications

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“…These apparent red shifts in peaks positions must be due to the fact that these peaks are on the uphill slope of the DXR absorption spectrum. When DXR was omitted the corresponding spectra, measured before and after H 2 O 2 , addition showed max at 412 and 430 nm, respectively, as expected for ferric and compound II forms of LPO (Jenzer et al, 1986). observation.…”

Section: Effect Of Salicylic Acid On Oxidation Of Anthracyclines By Msupporting

confidence: 59%

“…The corresponding spectral lines intersect at 421 nm, consistent with conversion of LPO-II to native LPO (Jenzer et al, 1986). During the LPO-II lifetime, the A 480 decreased by ⌬A 480 ϭ 0.041, which corresponds to the loss of 3.6 M DXR (Fig.…”

Section: Effect Of Salicylic Acid On Oxidation Of Anthracyclines By Mmentioning

confidence: 56%

“…The concentrations of the reactants were determined spectrophotometrically using appropriate extinction coefficients, ⑀ 240 ϭ 39. (Jenzer et al, 1986), and ⑀ 480 ϭ 1.15 ϫ 10 4 M Ϫ1 cm Ϫ1 for DNR(DXR) (Chaires et al, 1982). Because DNR and DXR tend to form dimers in aqueous solutions, in the present study, they were used in low micromolar concentrations (Ͻ10 M) to assure that they were present predominantly as monomers.…”

Section: Methodsmentioning

confidence: 99%

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Oxidation of Anthracyclines by Peroxidase Metabolites of Salicylic Acid

Reszka

Britigan

Britigan³

2005

J Pharmacol Exp Ther

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Oxidation of anthracyclines leads to their degradation and inactivation. This process is carried out by peroxidases in the presence of a catalytic cofactor, a good peroxidase substrate. Here, we investigated the effect of salicylic acid, a commonly used antiinflammatory and analgesic agent, on the peroxidative metabolism of anthracyclines. We report that at pharmacologically relevant concentrations, salicylic acid stimulates oxidation of daunorubicin and doxorubicin by myeloperoxidase and lactoperoxidase systems and that efficacy of the process increases markedly on changing the pH from 7 to 5. This pH dependence is positively correlated with the ease with which salicylic acid itself undergoes metabolic oxidation and involves the neutral form of the acid (pK a ϭ 2.98). When salicylic acid reacted with a peroxidase and H 2 O 2 at acid pH (anthracyclines omitted), a new metabolite with absorption maximum at 412 nm was formed. This metabolite reacted with anthracyclines causing their oxidation. It was tentatively assigned to biphenyl quinone, formed by oxidation of biphenol produced by dimerization of salicylic acid-derived phenoxyl radicals. The formation of this product was inhibited in a concentration-dependent manner by the anthracyclines, suggesting their scavenging of the salicylate phenoxyl radicals. Altogether, this study demonstrates that oxidation of anthracyclines is mediated by peroxidase metabolites of salicylic acid, such as phenoxyl radicals and the biphenol quinone. Given that cancer patients undergoing anthracycline chemotherapy may be administered salicylic acid-based drugs to control pain and fever, our results suggest that liberated salicylic acid could interfere with anticancer and/or cardiotoxic actions of the anthracyclines.Acetylsalicylic acid (aspirin, ASA) (Fig.

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Section: Effect Of Salicylic Acid On Oxidation Of Anthracyclines By Msupporting

confidence: 59%

Section: Effect Of Salicylic Acid On Oxidation Of Anthracyclines By Mmentioning

confidence: 56%

Section: Methodsmentioning

confidence: 99%

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Oxidation of Anthracyclines by Peroxidase Metabolites of Salicylic Acid

Reszka

Britigan

Britigan³

2005

J Pharmacol Exp Ther

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“…Compound II of LPO is predominant whenever LPO is exposed to a small excess of H 2 O 2 (21,(43)(44)(45). In this work, we prepared compound II by adding H 2 O 2 to the ferric enzyme at a molar ratio of 2:1.…”

Section: Effect Of Gsh On the Spectrum Of Compound II Of Lpo In The Pmentioning

confidence: 99%

Protein Radical Formation during Lactoperoxidase-mediated Oxidation of the Suicide Substrate Glutathione

Guo

Detweiler

Mason

2004

Journal of Biological Chemistry

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A novel anti-5,5-dimethyl-1-pyrroline N-oxide (DMPO) polyclonal antiserum that specifically recognizes protein radical-derived DMPO nitrone adducts has been developed. In this study, we employed this new approach, which combines the specificity of spin trapping and the sensitivity of antigen-antibody interactions, to investigate protein radical formation from lactoperoxidase (LPO). When LPO reacted with GSH in the presence of DMPO, we detected an LPO radical-derived DMPO nitrone adduct using enzyme-linked immunosorbent assay and Western blotting. The formation of this nitrone adduct depended on the concentrations of GSH, LPO, and DMPO as well as pH values, and GSH could not be replaced by H 2 O 2 . The level of this nitrone adduct was decreased significantly by azide, catalase, ascorbate, iodide, thiocyanate, phenol, or nitrite. However, its formation was unaffected by chemical modification of free cysteine, tyrosine, and tryptophan residues on LPO. ESR spectra showed that a glutathiyl radical was formed from the LPO/GSH/DMPO system, but no protein radical adduct could be detected by ESR. Its formation was decreased by azide, catalase, ascorbate, iodide, or thiocyanate, whereas phenol or nitrite increased it. GSH caused marked changes in the spectrum of compound II of LPO, indicating that GSH binds to the heme of compound II, whereas phenol or nitrite prevented these changes and reduced compound II back to the native enzyme. GSH also dose-dependently inhibited the peroxidase activity of LPO as determined by measuring 2,2 -azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) oxidation. Taken together, these results demonstrate that the GSH-dependent LPO radical formation is mediated by the glutathiyl radical, possibly via the reaction of the glutathiyl radical with the heme of compound II to form a heme-centered radical trapped by DMPO.

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“…LPO (from bovine milk; EC 1.11.1.7) and all other chemicals (hydrogen peroxide, 30%), ascorbic acid (AA), methimazole (1-methyl-3H-imidazole-2-thione), dapsone (diamino-diphenyl sulfone), and diethylenetriamine pentaacetic acid (DTPA) were obtained from Sigma-Aldrich (St. Louis, MO). LPO concentration was determined using ε 412 of 1.12 ϫ 10 5 M Ϫ1 ⅐ cm Ϫ1 (Jenzer et al, 1986). MPO from human leukocytes [lyophilized powder, 25 U, RZ (reinheit zahl purity value) (A 429 /A 280 ) of 0.61] was obtained from Axxora, LLC (San Diego, CA) and reconstituted with 0.25 ml of distilled water before use.…”

Section: Methodsmentioning

confidence: 99%

Airway Peroxidases Catalyze Nitration of the β₂-Agonist Salbutamol and Decrease Its Pharmacological Activity

Reszka

Sallans

Macha

et al. 2010

J Pharmacol Exp Ther

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␤ 2 -Agonists are the most effective bronchodilators for the rapid relief of asthma symptoms, but for unclear reasons, their effectiveness may be decreased during severe exacerbations. Because peroxidase activity and nitrogen oxides are increased in the asthmatic airway, we examined whether salbutamol, a clinically important ␤ 2 -agonist, is subject to potentially inactivating nitration. When salbutamol was exposed to myeloperoxidase, eosinophil peroxidase or lactoperoxidase in the presence of hydrogen peroxide (H 2 O 2 ) and nitrite (NO 2 Ϫ ), both absorption spectroscopy and mass spectrometry indicated formation of a new metabolite with features expected for the nitrated drug. The new metabolites showed an absorption maximum at 410 nm and pK a of 6.6 of the phenolic hydroxyl group. In addition to nitrosalbutamol (m/z 285.14), a salbutamol-derived nitrophenol, formed by elimination of the formaldehyde group, was detected (m/z 255.13) by mass spectrometry. It is noteworthy that the latter metabolite was detected in exhaled breath condensates of asthma patients receiving salbutamol but not in unexposed control subjects, indicating the potential for ␤ 2 -agonist nitration to occur in the inflamed airway in vivo. Salbutamol nitration was inhibited in vitro by ascorbate, thiocyanate, and the pharmacological agents methimazole and dapsone. The efficacy of inhibition depended on the nitrating system, with the lactoperoxidase/H 2 O 2 /NO 2 Ϫ being the most affected. Functionally, nitrated salbutamol showed decreased affinity for ␤ 2 -adrenergic receptors and impaired cAMP synthesis in airway smooth muscle cells compared with the native drug. These results suggest that under inflammatory conditions associated with asthma, phenolic ␤ 2 -agonists may be subject to peroxidase-catalyzed nitration that could potentially diminish their therapeutic efficacy.

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The role of superoxide radicals in lactoperoxidase-catalysed H2O2 — metabolism and in irreversible enzyme inactivation

Cited by 26 publications

References 4 publications

Oxidation of Anthracyclines by Peroxidase Metabolites of Salicylic Acid

Oxidation of Anthracyclines by Peroxidase Metabolites of Salicylic Acid

Protein Radical Formation during Lactoperoxidase-mediated Oxidation of the Suicide Substrate Glutathione

Airway Peroxidases Catalyze Nitration of the β₂-Agonist Salbutamol and Decrease Its Pharmacological Activity

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The role of superoxide radicals in lactoperoxidase-catalysed H2O2 — metabolism and in irreversible enzyme inactivation

Cited by 26 publications

References 4 publications

Oxidation of Anthracyclines by Peroxidase Metabolites of Salicylic Acid

Oxidation of Anthracyclines by Peroxidase Metabolites of Salicylic Acid

Protein Radical Formation during Lactoperoxidase-mediated Oxidation of the Suicide Substrate Glutathione

Airway Peroxidases Catalyze Nitration of the β2-Agonist Salbutamol and Decrease Its Pharmacological Activity

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Product

Resources

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Airway Peroxidases Catalyze Nitration of the β₂-Agonist Salbutamol and Decrease Its Pharmacological Activity