Reactive intermediates in the oxidation of hydralazine by HOCl: the major oxidant generated by neutrophils

Hofstra, Angela H.; Uetrecht, Jack

doi:10.1016/0009-2797(93)90008-m

Cited by 16 publications

(12 citation statements)

References 43 publications

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“…Our results suggest a necessity for formation of a three-electron oxidation product favored by acidic conditions in order to cause DNA damage. Consistent with other hypotheses (18), a lower pH appears to stabilize an intermediate, permitting further oxidation of that species to one capable of causing DNA strand breakage. The increase in DNA damage as the pH decreased from 7.0 to 5.0 suggests this may be the case.…”

Section: Discussionsupporting

confidence: 85%

“…Previous work by Hofstra and Uetrecht () has shown that there is a pH-dependent formation of specific intermediates. It was proposed that, at low pH, formation of both the diazene and diazonium ion was favored, and that the diazonium ion may be the damaging oxidized metabolite of hydralazine ( , ). Our results suggest a necessity for formation of a three-electron oxidation product favored by acidic conditions in order to cause DNA damage.…”

Section: Discussionmentioning

confidence: 99%

“…Possible explanations for the inability of certain chemicals to serve as effective mediators could be that an essential part of this process involves the type of interaction between the mediator and the enzyme, or simply the reaction rate for the particular substrate mediator (8). This may be the case with intermediates of hydralazine that are unstable and do not exist for significant time periods (18); however, DNA damage requires that these intermediates be oxidized. Both thioridazine and chlorpromazine, which enhance DNA damage, serve as excellent reductants of HRP compound I and compound II, far better than triflupromazine, ABTS, or phenol (data not shown) (8).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, hydralazine has been shown to be genotoxic to isolated hepatocytes (15), mutagenic in bacterial test systems (16), and carcinogenic to mice (17). The oxidative metabolism of hydralazine and other hydrazines to specific intermediates, possibly catalyzed by peroxidases, has been suggested to be essential to the development of such situations (18). Both metal-catalyzed oxidation of hydralazine as well as peroxidasecatalyzed oxidation have been shown to result in degradation of 32 P-labeled DNA, although peroxidases are rather inefficient (12).…”

Section: Introductionmentioning

confidence: 99%

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Peroxidase Substrates Stimulate the Oxidation of Hydralazine to Metabolites Which Cause Single-Strand Breaks in DNA

Reilly

Aust

1997

Chem. Res. Toxicol.

177

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Hydrazines are believed to be oxidized by peroxidases to reactive intermediates responsible for a variety of adverse side effects including cancer and drug-induced lupus. However, hydrazines are regarded as a poor peroxidase substrates because inactivation of the peroxidase occurs during oxidation of these compounds. We have investigated the hypothesis that efficient peroxidase substrates, termed mediators, may stimulate peroxidase-catalyzed oxidation of hydrazines to intermediates capable of causing DNA damage. Oxidation of hydralazine by horseradish peroxidase was stimulated, enzyme inactivation was significantly decreased, and DNA strand breakage was enhanced by the addition of chlorpromazine. Similar results were obtained using other peroxidases, mediators, and hydrazine derivatives. DNA damage required the addition of a minimum of 3 equiv of hydrogen peroxide, suggesting the involvement of a three-electron oxidation product of hydralazine in DNA damage. Efficient substrates may therefore play a critical role in peroxidase-dependent oxidative metabolism and subsequent damage to biological macromolecules by certain chemicals.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Peroxidase Substrates Stimulate the Oxidation of Hydralazine to Metabolites Which Cause Single-Strand Breaks in DNA

Reilly

Aust

1997

Chem. Res. Toxicol.

177

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“…Thus, while end products of these reactions have been determined, reactive intermediates produced by such reactions have not yet been identified (10,11,15). Although these intermediates remain unidentified, recent work with hydralazine by another group suggests that a diazene and a diazonium salt may be reactive intermediates formed during hydralazine oxidation by HOCl (18). The oxidation of hydrazine-containing drugs in a number of other biological systems results in the formation of a number of free-radical species (1,2).…”

mentioning

confidence: 99%

Free Radicals Produced during the Oxidation of Hydrazines by Hypochlorous Acid

Goodwin

Aust

Grover

1996

Chem. Res. Toxicol.

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Hypochlorous acid (HOCl) derived from activated neutrophils and monocytes has been implicated in the activation of hydrazine-containing drugs to toxic intermediates. However, reactive intermediates formed during the reaction between HOCl and these drugs have not been identified. We investigated the oxidation of the hydrazine derivatives isoniazid, iproniazid, and hydralazine by HOCl. The reaction between HOCl and all three hydrazines resulted in O2 consumption, indicating that free radicals were produced, but the rate and extent of O2 consumption were different for each hydrazine. Moreover, reduction of nitroblue tetrazolium (NBT) was observed only during the reaction between HOCl and isoniazid, suggesting that different radical species may be produced from HOCl reaction with each hydrazine. The oxidation of iproniazid by HOCl in the presence of the radical trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO) resulted in the formation of a carbon-centered radical adduct. In contrast, the reaction between HOCl and hydralazine resulted in the formation of a nitrogen-centered DMPO radical adduct. The oxidation of isoniazid by HOCl resulted in the formation of two oxygen-centered radical adducts, DMPO-OOH and DMPO-OH. Myeloperoxidase-catalyzed oxidation of these hydrazines in the presence of Cl- and H2O2 produced radical species that were identical to those observed with HOCl. Thus, some of the toxic side effects of these drugs may be the result of the production of free-radical intermediates from reaction with neutrophil-derived oxidants, such as HOCl. The types of radicals produced and the consequences of generating these reactive species are discussed.

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Role of Reactive Metabolites in Drug‐Induced Toxicity – The Tale of Acetaminophen, Halothane, Hydralazine, and Tienilic Acid

Kalgutkar

Dalvie

Obach

et al. 2012

Reactive Drug Metabolites

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Reactive intermediates in the oxidation of hydralazine by HOCl: the major oxidant generated by neutrophils

Cited by 16 publications

References 43 publications

Peroxidase Substrates Stimulate the Oxidation of Hydralazine to Metabolites Which Cause Single-Strand Breaks in DNA

Peroxidase Substrates Stimulate the Oxidation of Hydralazine to Metabolites Which Cause Single-Strand Breaks in DNA

Free Radicals Produced during the Oxidation of Hydrazines by Hypochlorous Acid

Role of Reactive Metabolites in Drug‐Induced Toxicity – The Tale of Acetaminophen, Halothane, Hydralazine, and Tienilic Acid

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