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

Abstract

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.

The antihypertensive drug hydralazine activates the intrinsic pathway of apoptosis and causes DNA damage in leukemic T cells

“…Moreover, similarly to genotoxic and nucleoside analogs drugs, hydralazine induces DNA damage in leukemic T cells, as determined by comet assay and activation of a DNA damage response. In line, induction of DNA damage by hydralazine has been recently reported in prostate cancer cells [36] and different authors have described the generation of radicals derived from the oxidation of hydralazine that may directly induce DNA damage [38, 39]. Regardless of the mechanism of DNA damage induction by hydralazine in leukemic T cells, this event must play an important role in apoptosis, as it is clearly evident after 12 hr treatment, concurrent with the activation of the apoptotic signaling pathway.…”

Surface-Enhanced Raman Spectroscopy-Based Approach for Ultrasensitive and Selective Detection of Hydrazine

“…5 Despite its common use, acute exposure to hydrazine causes severe damage to the liver, kidneys, and central nervous system in humans. 2,6,7 The U.S. Environmental Protection Agency (EPA), therefore, has classified hydrazine as Group B2, probable human carcinogen, and set its threshold limit value (TLV) to 10 ppb (3.1 × 10 −7 M). 8 Because of the widespread use of hydrazine, much effort has been devoted to the development of sensitive and selective analytical methods to detect trace levels of hydrazine.…”

Hydrazine Sensor Based on Co3O4/rGO/Carbon Cloth Electrochemical Electrode

“…[ 3,4 ] However, hydrazine and its derivatives have also been recognized as carcinogenic and hepatotoxic substances, which could cause kidney and liver diseases, even genetic damages or cancer through respiratory system, digestive system, and skin permeation to our body. [ 2,5,6 ] Therefore, effective and sensitive detection of hydrazine is practically crucial to environmental and biological analysis. Until now, a lot of methods have been explored for the detection of hydrazine, including chemiluminescence, [ 7 ] coulometric, [ 8 ] spectrophotometric methods, [ 9 ] and electrochemical technique.…”