3-Methylindole-induced splenotoxicity: Biochemical mechanisms of cytotoxicity

3-Methylindole (3-MI) is a pneumotoxic metabolite of l-tryptophan that can form in the digestive tracts of humans and ruminants as a result of microbial protein metabolism. Alternatively, human lungs can be directly exposed to 3-MI formed during protein pyrolysis and inhalation of tobacco smoke. 3-M...

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Veröffentlicht in:Toxicology and applied pharmacology 1991-07, Vol.109 (3), p.375-390
Hauptverfasser: Updyke, Lawrence W., Yoon, Hyunah L., Kiorpes, Anthony L., Robinson, J.Paul, Pfeifer, Richard W., Marcus, Craig B.
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Sprache:eng
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Zusammenfassung:3-Methylindole (3-MI) is a pneumotoxic metabolite of l-tryptophan that can form in the digestive tracts of humans and ruminants as a result of microbial protein metabolism. Alternatively, human lungs can be directly exposed to 3-MI formed during protein pyrolysis and inhalation of tobacco smoke. 3-MI has been shown to cause acute lung injury in both ruminants and rodents. The present studies demonstrate that the spleen is also a target for 3-MI-induced toxicity. A dose-dependent decrease in splenic weight (24–75%) and nucleated splenic cell number (22–68%) was observed 24 hr after intraperitoneal injection of 3-MI (50–300 mg/kg) to intact and adrenalectomized rats. These findings were associated with significant alterations in splenic histopathology. Mice appeared less affected by 3-MI than rats as no splenotoxicity was observed at doses less than 200 mg/kg. Other mono- and dimethyl-substituted indoles did not decrease mouse spleen cell numbers when administered in vivo. Phenobarbital pretreatment in vivo protected against 3-MI-induced splenotoxicity, suggesting a role for cytochrome P450-mediated metabolism of 3-MI in the splenotoxicity of this compound. Exposure of rat or mouse splenic cells to 3-MI (1 m m) in vitro resulted in toxic changes over 24 hr. However, equimolar concentrations of the structurally related mono- and dimethylindoles were also toxic in vitro, and preincubation with a variety of inhibitors of cytochrome P450 or prostaglandin synthase in vitro failed to protect against 3-MI-mediated toxicity to splenic cells in culture. These results suggest mechanisms of 3-MI splenotoxicity also exist that do not require bioactivation, and indicate a possible role for alkylindoles in suppression of immune function.
ISSN:0041-008X
1096-0333
DOI:10.1016/0041-008X(91)90001-U