Genotoxicity of the Antihypertensive Drugs Hydralazine and Dihydralazine

Williams, Gary M.; Mazué, G; McQueen, Charlene A.; Shimada, Tomiko

doi:10.1126/science.7423193

Cited by 51 publications

(16 citation statements)

References 21 publications

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“…In this study, we have used up to a five-fold molar excess of hydralazine to ensure effective trapping in tissue. Higher concentrations were not used because of previous reports of the toxic effects of concentrations in excess of 1 mmol/L in vitro (Williams et al 1980;Weglarz and Bartosz 1991;Runge-Morris et al 1994). Although these concentrations could not be achieved in serum in vivo, as the concentration following i.v.…”

Section: Discussionmentioning

confidence: 99%

Hydralazine inhibits compression and acrolein‐mediated injuries in ex vivo spinal cord

Hamann¹,

Nehrt²,

Ouyang³

et al. 2007

Journal of Neurochemistry

115

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Reactive oxygen species (ROS) and lipid peroxidation (LPO) have been associated with numerous diseases that few other pathological factors can match, including aging, neoplasia, trauma, and ischemia-reperfusion injury (Halliwell and Gutteridge 1999). The mechanism of involvement of LPO has been an area of intense research aiming to prevent, slow down, and even reverse the development of various diseases. In the case of spinal cord injury, it is well established that LPO plays an important role in neuronal degeneration, cell death, and overall functional deficits (Hall 1989(Hall , 1991Hall and Braughler 1993). This is believed due in part to that fact that neuronal cells contain a relatively large proportion of polyunsaturated fatty acids and are rich in mitochondria, both of which are a potential target and source of free radicals. Because of these unique features, the CNS is particularly vulnerable to oxidative injury. In spite of strong evidence suggesting that post-trauma oxidative stress plays a critical role in the pathogenesis of spinal cord injury, conventional strategies aiming to scavenge free radicals have largely failed to produce any effective treatment that can curtail oxidative injury. Hence, further understanding of the mechanisms of oxidative stress and identification of a novel and more effective target is highly warranted and desirable.In addition to the much studied ROS, highly reactive a,b-unsaturated aldehydes, including malondialdehyde, 4-hydroxynonenal (HNE), and acrolein, are produced as a byproduct of LPO (Witz 1989;Esterbauer et al. 1991;Uchida 1999;O'Brien et al. 2005). Among them, acrolein has been shown to be by far the most reactive with various biomolecules including proteins, DNA, and glutathione, and reacts 110-150 times faster with glutathione than HNE or Abbreviations used: AD, Alzheimer's disease; CAP, compound action potential conduction; DTNB, 5,5¢-Dithiobis (2-nitrobenzoic acid); HE, dihydroethidium; HNE, 4-hydroxynonenal; LDH, lactate dehydrogenase; LPO, lipid peroxidation; PB, phosphate buffer; PBS, phosphatebuffered saline; ROS, reactive oxygen species; SOD, superoxide dismutase; TMR, tetramethyl rhodamine dextran. AbstractWe have previously shown that acrolein, a lipid peroxidation byproduct, is significantly increased following spinal cord injury in vivo, and that exposure to neuronal cells results in oxidative stress, mitochondrial dysfunction, increased membrane permeability, impaired axonal conductivity, and eventually cell death. Acrolein thus may be a key player in the pathogenesis of spinal cord injury, where lipid peroxidation is known to be involved. The current study demonstrates that the acrolein scavenger hydralazine protects against not only acrolein-mediated injury, but also compression in guinea pig spinal cord ex vivo. Specifically, hydralazine (500 lmol/L to 1 mmol/L) can significantly alleviate acrolein (100-500 lmol/ L)-induced superoxide production, glutathione depletion, mitochondrial dysfunction, loss of membrane integrity, and reduced compound act...

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Section: Discussionmentioning

confidence: 99%

Hydralazine inhibits compression and acrolein‐mediated injuries in ex vivo spinal cord

Hamann¹,

Nehrt²,

Ouyang³

et al. 2007

Journal of Neurochemistry

115

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“…The reaction product of hydralazine with acrolein-protein adducts has also been characterized (Burcham et al 2004). Previous studies (Williams et al 1980;Weglarz and Bartosz 1991;Runge-Morris et al 1994) report toxic effects of hydralazine concentrations in excess of 1 mM in vitro.…”

Section: Acrolein Scavengingmentioning

confidence: 99%

Acrolein scavenging: a potential novel mechanism of attenuating oxidative stress following spinal cord injury

Hamann

Shi

2009

Journal of Neurochemistry

110

117

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It has long been established that oxidative stress plays a critical role in the pathophysiology of spinal cord injury, and represents an important target of therapeutic intervention following the initial trauma. However, free radical scavengers have been largely ineffective in clinical trials, and as such a novel target to attenuate oxidative stress is highly warranted. In addition to free radicals, peroxidation of lipid membranes following spinal cord injury (SCI) produces reactive aldehydes such as acrolein. Acrolein is capable of depleting endogenous antioxidants such as glutathione, generating free radicals, promoting oxidative stress, and damaging proteins and DNA. Acrolein has a significantly longer half-life than the transient free radicals, and thus may represent a potentially better target of therapeutic intervention to attenuate oxidative stress. There is growing evidence, from our lab and others, to suggest that reactive aldehydes such as acrolein play a critical role in oxidative stress and SCI. The focus of this review is to summarize the cellular and biochemical mechanisms of acrolein-induced membrane damage, mitochondrial injury, oxidative stress, cell death, and functional loss. Evidence will also be presented to suggest that acrolein scavenging may be a novel means of therapeutic intervention to attenuate oxidative stress and improve recovery following traumatic SCI.

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“…Individuals that develop this reaction have antinuclear antibodies as well as antibodies to DNA and nucleoproteins (6)(7)(8)(9)(10)(11)(12)(13). In vitro studies have also demonstrated interaction of systemic lupus erythematosus-inducing drugs with DNA (11,14,15).In the metabolism ofxenobiotics, N-acetylation is a step that can be followed by reactions such as N-hydroxylation and esterification, resulting in the generation of reactive metabolites that undergo covalent binding with cellular macromolecules, including DNA (16,17). Chemicals that can be acetylated and that also form covalent adducts with DNA include procainamide (18,19), isoniazid (20), and hydralazine (15), as well as the aromatic amine carcinogens, benzidine (21, 22), 2-aminofluorene, and 4-aminobiphenyl (23).…”

mentioning

confidence: 99%

“…Chemicals that can be acetylated and that also form covalent adducts with DNA include procainamide (18,19), isoniazid (20), and hydralazine (15), as well as the aromatic amine carcinogens, benzidine (21,22), 2-aminofluorene, and 4-aminobiphenyl (23). Adduct formation by chemicals can be mediated by the enzymatic removal of the N-acetyl moiety (24,25), and evidence in the rabbit suggests that this reaction and the initial acetylation step are properties of the same enzyme (26).…”

mentioning

confidence: 99%

Relationship between the genetically determined acetylator phenotype and DNA damage induced by hydralazine and 2-aminofluorene in cultured rabbit hepatocytes.

McQueen

Maslansky

Glowinski

et al. 1982

Proc. Natl. Acad. Sci. U.S.A.

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The relationship between acetylation rates of rabbit hepatocytes and their susceptibility to genotoxicity by DNAdamaging chemicals that undergo N-acetylation was studied in primary cultures of hepatocytes from New Zealand White rabbits that have a genetically determined difference in acetylation rates. Hepatocytes from rapid and slow acetylator rabbits maintained in culture the difference in acetylation rates that existed in viva DNA repair, an index of DNA damage, was produced by hydralazine in hepatocytes from slow acetylator rabbits but not in those from rapid acetylators. In contrast to these results, hepatocytes from rapid acetylators were more sensitive than those from slow acetylators to toxicity from the carcinogen 2-aminofluorene and displayed greater amounts of DNA repair. The amount of DNA repair measured with either chemical was dose dependent. These phenotype-dependent differences in the genotoxicity of two DNAdamaging chemicals provide evidence for the role of the acetylation polymorphism as a factor in determining susceptibility to toxicity, and perhaps carcinogenicity, of these chemicals. N-Acetylation rates of xenobiotics are under polymorphic genetic control in both humans and rabbits, resulting in individuals being either rapid or slow acetylators (1-5). This trait has been linked to toxicity and damage to DNA by chemicals of the aromatic amine or hydrazine type (6). For example, slow acetylator individuals are more likely than rapid acetylators to develop drug-related systemic lupus erythematosus (6-8). Individuals that develop this reaction have antinuclear antibodies as well as antibodies to DNA and nucleoproteins (6)(7)(8)(9)(10)(11)(12)(13). In vitro studies have also demonstrated interaction of systemic lupus erythematosus-inducing drugs with DNA (11,14,15).In the metabolism ofxenobiotics, N-acetylation is a step that can be followed by reactions such as N-hydroxylation and esterification, resulting in the generation of reactive metabolites that undergo covalent binding with cellular macromolecules, including DNA (16,17). Chemicals that can be acetylated and that also form covalent adducts with DNA include procainamide (18,19), isoniazid (20), and hydralazine (15), as well as the aromatic amine carcinogens, benzidine (21, 22), 2-aminofluorene, and 4-aminobiphenyl (23). Adduct formation by chemicals can be mediated by the enzymatic removal of the N-acetyl moiety (24,25), and evidence in the rabbit suggests that this reaction and the initial acetylation step are properties of the same enzyme (26).Because a difference in the acetylation rate can alter the proportion ofspecific metabolites that are formed (27), it is possible that genotoxicity-i. e., damage to DNA (28)-by substrates of N-acetyltransferase could be affected by the amount of acetylation. In order to investigate this possibility, we developed a model system that permitted measurement of both N-acetyltransferase activity and DNA damage in the same cells, using hepatocytes, which represent a major tissue of acetylation (...

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Genotoxicity of the Antihypertensive Drugs Hydralazine and Dihydralazine

Cited by 51 publications

References 21 publications

Hydralazine inhibits compression and acrolein‐mediated injuries in ex vivo spinal cord

Hydralazine inhibits compression and acrolein‐mediated injuries in ex vivo spinal cord

Acrolein scavenging: a potential novel mechanism of attenuating oxidative stress following spinal cord injury

Relationship between the genetically determined acetylator phenotype and DNA damage induced by hydralazine and 2-aminofluorene in cultured rabbit hepatocytes.

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