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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548516/
J Drug Metab Toxicol. Author manuscript; available in PMC 2019 Jun 4.
Published in final edited form as:
J Drug Metab Toxicol. 2014; 5(3): 168.
Published online 2014 Jul 8. doi: 10.4172/2157-7609.1000168
PMCID: PMC6548516
NIHMSID: NIHMS1528568
PMID: 31171988
Birandra K. Sinha and Ronald P. Mason
Author information Copyright and License information Disclaimer
Hydrazine derivatives are environmental and food pollutants but are also important because of their use in medicine for the treatment of tuberculosis and cancer. However, hydrazines also pose significant health risks to humans as they are mutagenic and carcinogenic. This review examines various metabolic pathways (enzymatic and non-enzymatic) of hydrazines for the formation of reactive species that bind to cellular macromolecules and lead to cellular dysfunction. It is believed that this biotransformation is responsible for the pharmacology and pathophysiology of hydrazine derivatives.
Many chemicals, either man-made or found in nature, undergo metabolic activation to exert their biological effects. Some of these effects are considered desirable because they are curative, e.g., affect a disease state and lead to a cure. However, there are many chemicals that induce significant undesirable effects (or toxicity) as a result of this metabolic biotransformation, resulting in severe organ toxicity, tumor formation, and in some cases, death [1]. Hydrazine and its derivatives, which are used as high energy rocket fuel, induce a variety of toxic insults, including hypoglycemia, disorders of the CNS, induction of systemic lupus erythematosus, and cancer [2–5]. Hydrazines are also found in tobacco and in edible mushrooms. Isoniazid and iproniazid, monoamine oxidase inhibitors, are in use for the treatment of tuberculosis and, until recently, as an antidepressant, respectively [6, 7]. Hydralazine is a potent arterial vasodilator and plays an important role in the management of hypertension and congestive heart failure [8]. Hydralazine is toxic and induces DNA damage, causes severe forms of systemic lupus erythematosus and has been shown to increase the incidence of lung tumors in mice [5, 9, 10]. Procarbazine is a chemotherapeutic agent used in the treatment of Hodgkin’s disease, malignant melanoma and brain tumors in children [11].
Because of the significance of hydrazine derivatives as environmental pollutants and food contaminants as well as their utility in medicine, significant research has been carried out to elucidate the mechanisms of toxicity of these compounds [2–13]. It has been suggested that metabolic activation of hydrazines leads to their toxicity, and various non-enzymatic and enzymatic systems have been identified [6, 7, 14–17]. Hydrazines undergo acetylation by N-acetyl transferase, in which an acetyl group is transferred from acetyl coenzyme A; the rate of acetylation of hydrazines can be fast or slow depending upon the concentrations of the enzyme and an individual’s phenotype [18]. People who are fast acetylators rapidly convert hydrazine to its acetyl form, thus either increasing or decreasing toxicity depending upon further metabolism of acetylhydrazine to reactive species [6, 7]. Furthermore, cytochrome P450 isozymes (1A1, 1A2, 2B1 and 2E2) have been shown to oxidize hydrazines to toxic intermediates that bind to cellular macromolecules [6, 7, 19]. This review discusses the various aspects of metabolic activations of certain hydrazines, formation of reactive intermediates (carbocations and free radicals), and their roles in in vivo toxicity.