Involvement of Free Radicals in the Mechanism of 3-Methylindole-Induced Pulmonary Toxicity: An Example of Metabolic Activation in Chemically Induced Lung Disease
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Medientyp:
E-Artikel
Titel:
Involvement of Free Radicals in the Mechanism of 3-Methylindole-Induced Pulmonary Toxicity: An Example of Metabolic Activation in Chemically Induced Lung Disease
Beteiligte:
Bray, Tammy M.;
Kubow, Stan
Erschienen:
National Institute of Environmental Health Sciences. National Institutes of Health. Department of Health, Education and Welfare, 1985
Beschreibung:
<p>3-Methylindole (3-MI) is a metabolite of tryptophan which causes acute pulmonary edema and emphysema in ruminants when administered orally or intravenously. 3-MI is metabolized by mixed-function oxidases to a reactive intermediate which may play a role in 3-MI-induced pneumotoxicity. Electron spintrapping techniques have been used to investigate the in vitro and in vivo formation of free radicals during 3-MI metabolism by goat lung. A nitrogen-centered free radical of 3-MI has been generated from 3-MI in goat lung microsomal incubations. Although a nitrogen-centered free radical can be generated chemically from most of the indolic compounds, only the 3-MI free radical can be generated enzymatically. The formation of the nitrogen-centered 3-MI free radical was followed by the appearance of a carbon-centered lipid radical in microsomal preparations. The findings that an identical carbon-centered free radical was generated by FeSo<sub>4</sub>in the microsomal system in the absence of 3-MI and that malonaldehyde formation is stimulated by 3-MI in microsomes led to the conclusion that 3-MI metabolism induces lipid peroxidation of microsomal membranes. The formation of 3-MI-induced lipid radicals was inhibited by vitamin E and glutathione. A carbon-centered radical was spin trapped in vivo in the lungs of goats infused with 3-MI. This radical had the same splitting constants as the carbon-centered lipid radical trapped in microsomal incubations containing 3-MI. This finding indicates that the metabolism of 3-MI in goat lung in vivo generates a lipid radical. When lung glutathione levels were depressed by pretreatment with diethylmaleate, tissue concentrations of the carbon-centered lipid radical were increased and 3-MI-induced pulmonary toxicity became more severe. These studies support the hypothesis that free radicals are involved in 3-MI-induced pneumotoxicity and that tissue glutathione plays an important role in the defense of the lung against 3-MI toxicity.</p>