Involvement of free radicals in the mechanism of 3-methylindole-induced pulmonary toxicity: an example of metabolic activation in chemically induced lung disease.
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 spin-trapping 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 FeSo4 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.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D001711:Biotransformation; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals; D006041:Goats; D007211:Indoles / Q000633:toxicity*; D007700:Kinetics; D008054:Lipid Peroxides / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008171:Lung Diseases / Q000139:chemically induced*; D010084:Oxidation-Reduction; D012862:Skatole / Q000378:metabolism / Q000633:toxicity*
D005609:Free Radicals; D007211:Indoles; D008054:Lipid Peroxides; D012862:Skatole