Toxicological Research on Hydrazine Dihydrochloride

Introduction

Hydrazine dihydrochloride, is primarily driven by their metabolic activation into reactive intermediates.  This biotransformation is a critical step in initiating the cascade of events that lead to cellular damage and dysfunction. [1]

Metabolic Activation and Reactive Species Formation

Hydrazine dihydrochloride undergo metabolic activation through both enzymatic and non-enzymatic pathways, leading to the formation of reactive species. Enzymatic metabolism can involve cytochrome P450 enzymes, which can generate reactive metabolites. Non-enzymatic pathways also contribute to the production of free radicals. [1]

 The metabolism of similar compounds of hydrazine dihydrochloride can produce reactive intermediates such as the diimide intermediate, a strong reducing agent. Studies on phenylhydrazine have also indicated the formation of phenyldiazine, phenyldiazonium, and the phenyl radical as reactive intermediates. The oxidation of hydrazine derivatives by substances like hypochlorous acid, which can be derived from neutrophils, can also produce free radicals. The specific type of radical produced can vary depending on the specific hydrazine derivative. For instance, the oxidation of iproniazid results in a carbon-centered radical, while hydralazine forms a nitrogen-centered radical. [2]

Binding to Cellular Macromolecules

Hydrazine dihydrochloride can bind to essential cellular macromolecules, including proteins and nucleic acids. This covalent binding can alter the structure and function of these molecules, leading to cellular dysfunction. For example, reactive intermediates from hydrazine metabolism have been shown to bind to cytochrome P450 enzymes, leading to their inactivation. This can, in turn, affect the metabolism of other substances. The binding of these reactive species to DNA is a key factor in the genotoxicity of hydrazine compounds. [3]

Mutagenicity and Carcinogenicity Research

Hydrazine dihydrochloride and other hydrazine salts have demonstrated positive results in a variety of genotoxicity tests, indicating their potential to cause genetic mutations and cancer. This compound has been shown to be a genotoxic agent in both in vitro and in vivo studies. It has tested positive in the Ames test, a bacterial reverse mutation assay, demonstrating its mutagenic potential. Furthermore, it has shown clastogenic effects, meaning it can cause structural changes to chromosomes, in mammalian chromosomal aberration tests. Studies using rat and mouse hepatocytes have also demonstrated the genotoxicity of various hydrazine derivatives, with mouse hepatocytes appearing to be more susceptible. [4]

Oxidative Stress Induction

Hydrazine dihydrochloride is recognized for its capacity to induce oxidative stress within biological systems.  This phenomenon is a key aspect of its toxicological profile, stemming from the generation of free radicals and reactive oxygen species (ROS).  The metabolic activation of hydrazine can lead to the formation of these reactive intermediates, which subsequently interact with essential cellular macromolecules like DNA and proteins. Research indicates that exposure to hydrazine leads to a cascade of events characteristic of oxidative stress. A primary effect is the depletion of cellular antioxidants, notably reduced glutathione (GSH).  Studies in primary rat hepatocytes have demonstrated that Hydrazine dihydrochloride exposure causes a significant decrease in GSH levels and a corresponding increase in its oxidized form.  This depletion compromises the cell's ability to neutralize harmful oxidants. The generation of ROS, such as hydrogen peroxide, increases in a dose-dependent manner following hydrazine exposure.  This surge in ROS contributes to lipid peroxidation, a process of cellular damage marked by the increased presence of substances like malondialdehyde (MDA).  Furthermore, hydrazine-induced oxidative stress can cause direct damage to genetic material, evidenced by the formation of 8-hydroxy-2′-deoxyguanosine (8-OHdG) DNA adducts.  Another distinct cellular response is the formation of megamitochondria, which are abnormally large and structurally irregular mitochondria thought to arise from membrane fusion triggered by free radicals.  The hepatotoxicity associated with hydrazine is largely attributed to this induction of oxidative stress. [5]

References:

[1] Sinha, B. K., & Mason, R. P. (2014). BIOTRANSFORMATION OF HYDRAZINE DERVATIVES IN THE MECHANISM OF TOXICITY. Journal of drug metabolism & toxicology, 5(3), 168. https://doi.org/10.4172/2157-7609.1000168

[2] Goodwin, D. C., Aust, S. D., & Grover, T. A. (1996). Free radicals produced during the oxidation of hydrazines by hypochlorous acid. Chemical research in toxicology, 9(8), 1333–1339. https://doi.org/10.1021/tx960108l

[3] Runge-Morris, M., Wu, N., & Novak, R. F. (1994). Hydrazine-mediated DNA damage: role of hemoprotein, electron transport, and organic free radicals. Toxicology and applied pharmacology, 125(1), 123–132. https://doi.org/10.1006/taap.1994.1056

[4] Mori, H., Sugie, S., Yoshimi, N., Iwata, H., Nishikawa, A., Matsukubo, K., Shimizu, H., & Hirono, I. (1988). Genotoxicity of a variety of hydrazine derivatives in the hepatocyte primary culture/DNA repair test using rat and mouse hepatocytes. Japanese journal of cancer research : Gann, 79(2), 204–211. https://doi.org/10.1111/j.1349-7006.1988.tb01578.x

[5] https://www.epa.gov/sites/default/files/2016-09/documents/hydrazine.pdf

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