Hydralazine and Other Hydrazine Derivatives and the Formation of DNA Adducts

Mathison, Brian H.; Murphy, Sharon E.; Shank, Ronald C.

doi:10.1006/taap.1994.1143

Cited by 21 publications

(10 citation statements)

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“…Accordingly, a variety of DNA-damage mechanisms have been proposed to explain the mutagenic action of 4 , including oxidation of the drug to a DNA-damaging diazonium ion, diazene radical, or aryl radical, nucleophilic addition to pyrimidine residues in DNA, and oxidative conversion of a formaldehyde-derived hydrazone adduct into a DNA-alkylating species. 13 − 17 However, no consensus has emerged regarding a chemical mechanism for the damage of cellular DNA by 4 .…”

Section: Introductionmentioning

confidence: 99%

Covalent Adduct Formation between the Antihypertensive Drug Hydralazine and Abasic Sites in Double- and Single-Stranded DNA

Melton

Lewis

Price

et al. 2014

Chem. Res. Toxicol.

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Hydralazine (4) is an antihypertensive agent that displays both mutagenic and epigenetic properties. Here, gel electrophoretic, mass spectroscopic, and chemical kinetics methods were used to provide evidence that medicinally relevant concentrations of 4 rapidly form covalent adducts with abasic sites in double- and single-stranded DNA under physiological conditions. These findings raise the intriguing possibility that the genotoxic properties of this clinically used drug arise via reactions with an endogenous DNA lesion rather than with the canonical structure of DNA.

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Section: Introductionmentioning

confidence: 99%

Covalent Adduct Formation between the Antihypertensive Drug Hydralazine and Abasic Sites in Double- and Single-Stranded DNA

Melton

Lewis

Price

et al. 2014

Chem. Res. Toxicol.

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“…This hydroxylamine product could react both with proteins and with DNA, introducing strand breaks in the latter (2). Alternatively it has been suggested that the reaction may involve reduction of the opposite, amide, end of the molecule, generating an amine with liberation of the toxic product, formamide (10).…”

mentioning

confidence: 99%

Structural and Mechanistic Studies of Escherichia coli Nitroreductase with the Antibiotic Nitrofurazone

Race

Lovering

Green

et al. 2005

Journal of Biological Chemistry

196

243

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The antibiotics nitrofurazone and nitrofurantoin are used in the treatment of genitourinary infections and as topical antibacterial agents. Their action is dependent upon activation by bacterial nitroreductase flavoproteins, including the Escherichia coli nitroreductase (NTR). Here we show that the products of reduction of these antibiotics by NTR are the hydroxylamine derivatives. We show that the reduction of nitrosoaromatics is enzyme-catalyzed, with a specificity constant ϳ10,000-fold greater than that of the starting nitro compounds. This suggests that the reduction of nitro groups proceeds through two successive, enzyme-mediated reactions and explains why the nitroso intermediates are not observed. The global reaction rate for nitrofurazone determined in this study is over 10-fold higher than that previously reported, suggesting that the enzyme is much more active toward nitroaromatics than previously estimated. Surprisingly, in the crystal structure of the oxidized NTR-nitrofurazone complex, nitrofurazone is oriented with its amide group, rather than the nitro group to be reduced, positioned over the reactive N5 of the FMN cofactor. Free acetate, which acts as a competitive inhibitor with respect to NADH, binds in a similar orientation. We infer that the orientation of bound nitrofurazone depends upon the redox state of the enzyme. We propose that the charge distribution on the FMN rings, which alters upon reduction, is an important determinant of substrate binding and reactivity in flavoproteins with broad substrate specificity.

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“…Agaritine is catalyzed in rat and mouse kidney homogenates by removal of the glutamyl group to yield reactive free hydrazine [ 54 , 55 ] which, after formylation to its corresponding hydrazone, may be activated both in vitro and in vivo to a methylating intermediate resulting in the formation of O 6 -methyl-(O 6 -mG) and N7-methylguanines (N7-mG) in DNA [ [56] , [57] , [58] ]. Additionally, 4-hydroxymethyl) benzenediazonium salt, a carcinogen in A. bisporus , generates a carbon-centered radical, the 4-(hydroxymethyl)phenyl radical, which causes DNA strand breaks [ 59 ].…”

Section: Hydrazinic Fungimentioning

confidence: 99%