Oxidative activation of benzidine and its derivatives by peroxidases.

Josephy, P. David

doi:10.1289/ehp.8564171

Cited by 36 publications

(17 citation statements)

References 42 publications

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“…Bladder transitional epithelial microsomes from dog, on addition of arachidonate, also catalyzed the binding ofbenzidine or o-dianisidine to DNA (103). The nature of the oxidation products including the first formed cation radical in a peroxidase-H202 catalyzed oxidation has been reviewed (104). The effects of DNA (105) on this reaction sequence are as follows.…”

Section: N-oxidationmentioning

confidence: 99%

Free-radical-mediated DNA binding.

O’Brien¹

1985

Environ Health Perspect

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Free-radical metabolites can be generated metabolically by a one-electron reductase-catalyzed reaction or a "peroxidase" catalyzed oxidation or by photoactivation of a wide variety of aromatic xenobiotics. Radicals may also be generated during lipid peroxidation. Some radicals can react with DNA or bind covalently or noncovalently as a dismutation product or as a dimer, trimer or polymeric product. Modification to the DNA can result in single-strand breaks, loss of template activity, and crosslinking. The binding can prevent enzymic digestion. In some cases, the radicals react with oxygen, resulting before conversion to DNA reactive oxygen species. Most radicals probably do not interact with DNA.

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Section: N-oxidationmentioning

confidence: 99%

Free-radical-mediated DNA binding.

O’Brien¹

1985

Environ Health Perspect

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“…The nature of the oxidation products including the first formed cation radical in a peroxidase-H202 catalyzed oxidation has been reviewed (104). Similar results were found in another system, i.e., prostaglandin synthetase-arachidonate (102).…”

Section: The Cation Radical For P-phenylenediamine (As Determined By mentioning

confidence: 58%

Free-Radical-Mediated DNA Binding

O’Brien¹

1985

Environmental Health Perspectives

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JSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range of content in a trusted digital archive. We use information technology and tools to increase productivity and facilitate new forms of scholarship. For more information about JSTOR, please contact support@jstor.org.. The National Institute of Environmental Health Sciences (NIEHS) andBrogan & Partners are collaborating with JSTOR to digitize, preserve and extend access to Environmental Health Perspectives.Free-radical metabolites can be generated metabolically by a one-electron reductase-catalyzed reaction or a "peroxidase" catalyzed oxidation or by photoactivation of a wide variety of aromatic xenobiotics. Radicals may also be generated during lipid peroxidation. Some radicals can react with DNA or bind covalently or noncovalently as a dismutation product or as a dimer, trimer or polymeric product. Modification to the DNA can result in singlestrand breaks, loss of template activity, and crosslinking. The binding can prevent enzymic digestion. In some cases, the radicals react with oxygen, resulting before conversion to DNA reactive oxygen species. Most radicals probably do not interact with DNA.

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“…In support of this hypothesis, evidence of DAPM metabolism by peroxidase enzymes has been demonstrated previously (27). In addition, COX-2 has been shown to be involved in the metabolism and bioactivation of benzidine, a molecule structurally very similar to DAPM (28). Moreover, in our earlier studies, DAPM-induced proliferation was inhibited by co-treatment with N -acetylcysteine (NAC), but this effect was not related to NAC’s ability to modulate cellular oxidative stress levels (6).…”

Section: Discussionmentioning

confidence: 99%

Role of COX-2 in the Bioactivation of Methylenedianiline and in Its Proliferative Effects in Vascular Smooth Muscle Cells

et al. 2011

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4,4′-Methylenedianiline (DAPM) is an aromatic diamine used directly in the production of polyurethane forms and epoxy resins, or as a precursor to MDI in the manufacture of some polyurethanes. In our prior experiments, we showed that chronic, intermittent treatment of female rats with DAPM resulted in vascular medial hyperplasia of pulmonary arteries. In addition, treatment of vascular smooth muscle cells (VSMC) in culture with DAPM increased rates of proliferation in a manner that was inhibited by cotreatment with N-acetylcysteine but was not associated with oxidative stress. We thus hypothesized that NAC treatment inhibited DAPM toxicity by competing for binding reactive intermediates formed through DAPM metabolism. Because the peroxidase enzyme cyclooxygenase is constitutively expressed in VSMC, and because cyclooxygenase is known to metabolize similar aromatic amines to electrophilic intermediates, we further hypothesized that DAPM-induced VSMC proliferation was dependent upon COX-1/2-mediated bioactivation. To test this hypothesis, we treated VSMC with DAPM and measured cell proliferation, COX-2 expression, COX-1/2 activity and levels of covalent binding. DAPM treatment resulted in a dose-dependent increase in proliferation that was abolished by co-treatment with the COX-2-selective inhibitor celecoxib. In addition, DAPM exposure increased rates of proliferation in VSMC isolated from wildtype but not COX-2 (−/−) mice. Paradoxically, treatment with DAPM reduced cellular production of PGE2 and PGF2α, but dose-dependently increased COX-2 protein levels. Covalent binding of [14C]-DAPM to VSMC biomolecules was greater in wildtype than in COX-2 (−/−) cells. However, covalent binding of [14C]-DAPM was not altered by cotreatment with a nonselective inhibitor of cytochromes P450. These studies thus suggest that DAPM-induced VSMC proliferation may be due to bioactivation of DAPM, perhaps through the action of cyclooxygenase. The data furthermore suggest that DAPM’s mechanism of action may possibly involve inhibition or suicide inactivation of COX-2. In addition, because we observed an increase in DAPM-induced VSMC proliferation in cells isolated from female compared to male rats, further studies into the potential interplay between DAPM, the estrogen receptor, and COX-2 seem warranted.

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Oxidative activation of benzidine and its derivatives by peroxidases.

Cited by 36 publications

References 42 publications

Free-radical-mediated DNA binding.

Free-radical-mediated DNA binding.

Free-Radical-Mediated DNA Binding

Role of COX-2 in the Bioactivation of Methylenedianiline and in Its Proliferative Effects in Vascular Smooth Muscle Cells

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