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Toxicologic Pathology
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Journal Article

Detection of Free Radical Intermediates in the Oxidative Metabolism of Carcinogenic Hydrazine Derivatives

Aldo Tomasi

Istituto di Patologia Generale di Modena, via Campi 287 41100 Modena, Italy and Instituto di Patologia Generale di Torino, Corso Raffaello 30, 10125 Torino, Italy

Emanuele Albano

Istituto di Patologia Generale di Modena, via Campi 287 41100 Modena, Italy and Instituto di Patologia Generale di Torino, Corso Raffaello 30, 10125 Torino, Italy

Barbara Botti

Istituto di Patologia Generale di Modena, via Campi 287 41100 Modena, Italy and Instituto di Patologia Generale di Torino, Corso Raffaello 30, 10125 Torino, Italy

Vanio Vannini

Istituto di Patologia Generale di Modena, via Campi 287 41100 Modena, Italy and Instituto di Patologia Generale di Torino, Corso Raffaello 30, 10125 Torino, Italy

Hydrazine derivatives are widely used in agriculture, in industry, as rocket propellants, and in medicine. Hydrazines also occur naturally in tobacco and mushrooms. Many hydrazines tested in animal studies appear to be carcinogenic and induce tumors in various target tissues in mice, hamsters, and rats. The use of hydrazine derivatives in humans is of ten complicated by adverse side-effects such as liver injury and rheumatoid arthritis. A number of studies have demonstrated that hydrazine derivatives are activated to reactive intermediates, such as free radicals, through a variety of cellular oxidative metabolic pathways. The aim of this work is to demonstrate the occurrence of free radical intermediates during the metabolic activation of various hydrazine derivatives and to characterize the enzymatic system(s) responsible for the activation to free radical species. The hydrazines studied are acetylhydrazine, isoniazid, isopropylhydrazine, iproniazid, methylhydrazine, 1,1-dimethylhydrazine, and 1,2-dimethylhydrazine. The model systems chosen are those of rat liver microsomes and isolated hepatocytes. Free radical intermediates have been demonstrated by the electron spin resonance spectroscopy coupled to spin trapping technique. The activation mechanism has been characterized using inhibitors of the mixed function oxidase system and of the FAD-dependent oxygenase system. Glutathione was able to scavenge, with high efficiency, the free radicals produced.

Toxicologic Pathology, Vol. 15, No. 2, 178-183 (1987)
DOI: 10.1177/019262338701500208
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