Scavenging effect of melatonin on hydroxyl radicals generated by alloxan

Brömme, Hans‐Jürgen; Mörke, Wolfgang; Peschke, Elmar; Ebelt, Henning; Peschke, D.

doi:10.1034/j.1600-0633.2002.290402.x

Cited by 99 publications

(62 citation statements)

References 36 publications

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“…In these studies, the quantity of urinary cyclic 3-OHM was increased when rats were supplemented with melatonin and rose even further when the rats were exposed to whole-body ionizing radiation, a physical agent known to generate dOH. Many other studies have con® rmed melatonin' s ability to detoxify dOH (Matuszak et al 1997 ;Susa et al 1997 ;Bandyopadhyay et al 2000 ;Bro$ mme et al 2000 ;Poeggeler et al 2002). The calculated biomolecular rate constant for the melatonin}dOH reaction is 0.6¬ 10 11 m 1 s 1 .…”

Section: Melatonin : Direct Scavenging Actionsmentioning

confidence: 80%

Melatonin: reducing the toxicity and increasing the efficacy of drugs

Reíter¹,

Tan²,

Sainz³

et al. 2002

Journal of Pharmacy and Pharmacology

378

300

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Melatonin (N-acetyl-5-methoxytryptamine) is a molecule with a very wide phylogenetic distribution from plants to man. In vertebrates, melatonin was initially thought to be exclusively of pineal origin ; recent studies have shown, however, that melatonin synthesis may occur in a variety of cells and organs. The concentration of melatonin within body uids and subcellular compartments varies widely, with blood levels of the indole being lower than those at many other sites. Thus, when de ning what constitutes a physiological level of melatonin, it must be de ned relative to a speci c compartment. Melatonin has been shown to have a variety of functions, and research in the last decade has proven the indole to be both a direct free radical scavenger and indirect antioxidant. Because of these actions, and possibly others that remain to be de ned, melatonin has been shown to reduce the toxicity and increase the ef cacy of a large number of drugs whose side effects are well documented. Herein, we summarize the bene cial effects of melatonin when combined with the following drugs: doxorubicin, cisplatin, epirubicin, cytarabine, bleomycin, gentamicin, ciclosporin, indometacin, acetylsalicylic acid, ranitidine, omeprazole, isoniazid, iron and erythropoietin, phenobarbital, carbamazepine, haloperidol, caposide-50, morphine, cyclophosphamide and L-cysteine. While the majority of these studies were conducted using animals, a number of the investigations also used man. Considering the low toxicity of melatonin and its ability to reduce the side effects and increase the ef cacy of these drugs, its use as a combination therapy with these agents seems important and worthy of pursuit.

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Section: Melatonin : Direct Scavenging Actionsmentioning

confidence: 80%

Melatonin: reducing the toxicity and increasing the efficacy of drugs

Reíter¹,

Tan²,

Sainz³

et al. 2002

Journal of Pharmacy and Pharmacology

378

300

View full text Add to dashboard Cite

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“…The reduction of alloxan to dialuric acid in the cell requires the presence of a suitable thiol, typically the tripeptide glutathione (GSH) to generate the redox cycling partner, dialuric acid, and oxidised glutathione (viii) [56,58]. The triketone structure of alloxan is vitally important for this two-step reaction with glutathione [59], which generates the alloxan radical as an intermediate product (ix-x).…”

Section: Beta Cell Toxicity and Diabetogenicity Of Alloxanmentioning

confidence: 99%

The mechanisms of alloxan- and streptozotocin-induced diabetes

2007

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Alloxan and streptozotocin are toxic glucose analogues that preferentially accumulate in pancreatic beta cells via the GLUT2 glucose transporter. In the presence of intracellular thiols, especially glutathione, alloxan generates reactive oxygen species (ROS) in a cyclic redox reaction with its reduction product, dialuric acid. Autoxidation of dialuric acid generates superoxide radicals, hydrogen peroxide and, in a final iron-catalysed reaction step, hydroxyl radicals. These hydroxyl radicals are ultimately responsible for the death of the beta cells, which have a particularly low antioxidative defence capacity, and the ensuing state of insulin-dependent 'alloxan diabetes'. As a thiol reagent, alloxan also selectively inhibits glucose-induced insulin secretion through its ability to inhibit the beta cell glucose sensor glucokinase. Following its uptake into the beta cells, streptozotocin is split into its glucose and methylnitrosourea moiety. Owing to its alkylating properties, the latter modifies biological macromolecules, fragments DNA and destroys the beta cells, causing a state of insulin-dependent diabetes. The targeting of mitochondrial DNA, thereby impairing the signalling function of beta cell mitochondrial metabolism, also explains how streptozotocin is able to inhibit glucose-induced insulin secretion.

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“…[2][3][4][5][6][7][8] One possible mechanism of alloxan activity assumes its reduction to dialuric acid, the process that can be effectively enhanced by physiological reagents such as NAD(P)H and GSH and by enzymatic means by the thioredoxin/NADPH-thioredoxin reductase or thioltransferase systems. [9][10][11][12][13][14][15][16] The subsequent oxidative decomposition of dialuric acid is thought to account for alloxan toxicity in the -cells through the oxidation stress. [17][18][19] Auto-oxidation of the dialuric acid has been shown to generate O 2 •-, H 2 O 2 , and, in the presence of suitable catalyst, • OH.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Aspects of Alloxan Diabetogenic Activity: A Key Role of Keto−Enol Inversion of Dialuric Acid on Ionization

et al. 2006

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The inversion of the keto-enol stability order of dialuric acid on ionization was calculated and verified experimentally. The radical cations in both forms were characterized. The spectrum of the keto form was observed upon direct ionization of dialuric acid under matrix conditions, whereas the enol form was formed upon a sequential electron-proton-proton attachment to alloxan under acidic aqueous condition. Facilitation of the one-electron oxidation of dialuric acid upon its enolization can result in a more effective formation of superoxide radical anion in the process of its auto-oxidation. This process is discussed in reference to the alloxan diabetogenic action. Both neutral keto and enol forms are energetically close, and under favorable conditions, the auto-oxidation of dialuric acid could involve participation of the enol form.

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Scavenging effect of melatonin on hydroxyl radicals generated by alloxan

Cited by 99 publications

References 36 publications

Melatonin: reducing the toxicity and increasing the efficacy of drugs

Melatonin: reducing the toxicity and increasing the efficacy of drugs

The mechanisms of alloxan- and streptozotocin-induced diabetes

Mechanistic Aspects of Alloxan Diabetogenic Activity: A Key Role of Keto−Enol Inversion of Dialuric Acid on Ionization

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