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-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 mM) 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.
Updyke
L W
LW
Department of Pharmacology and Toxicology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907.
Yoon
H L
HL
Kiorpes
A L
AL
Robinson
J P
JP
Pfeifer
R W
RW
Marcus
C B
CB
D000315:Adrenalectomy; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D012862:Skatole / Q000633:toxicity*; D013154:Spleen / Q000187:drug effects* / Q000473:pathology
D012862:Skatole