Organ-selective switching of 3-methylindole toxicity by glutathione depletion.
A high dose (550 mg/kg) of 3-methylindole (3MI) specifically damaged pulmonary tissue in Swiss-Webster mice without causing any hepatic or renal necrosis. When a glutathione depleter, L-buthionine-(S,R)-sulfoximine (BSO, 1.0 mmol/kg), was administered to mice 3 hr before a low dose of 3-methylindole (75 mg/kg), significant renal damage was observed by histopathological examination after 4 hr. The nephrotoxicity occurred without any observable pathological damage to lung tissues. Increased doses of BSO caused dose-dependent increases in renal toxicity. A low dose of BSO (1.0 mmol/kg) caused no depletion of renal glutathione levels, a large depletion of hepatic glutathione levels (60% of control values), and much larger increases in covalent binding of [methyl-14C]3-methylindole to renal tissues (3.4-fold) than to hepatic tissues (1.5-fold) or pulmonary tissues (2.1-fold). No evidence of hepatic or pulmonary histopathological damage was observed at any dose of BSO with 75 mg/kg 3MI. These results indicate that a shift in organ selectivity of 3MI-induced toxicity from pulmonary to renal sites occurs as a result of glutathione depletion in hepatic tissues. The production of a toxic metabolite in the livers of glutathione-depleted mice that is circulated to susceptible renal cells may be the mechanism of this interesting organ-selective shift in toxicity of 3MI.
Yost
G S
GS
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City.
Kuntz
D J
DJ
McGill
L D
LD
D000818:Animals; D019328:Buthionine Sulfoximine; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000032:analysis / Q000502:physiology*; D007211:Indoles / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D009928:Organ Specificity; D011485:Protein Binding; D012862:Skatole / Q000378:metabolism / Q000633:toxicity*
D007211:Indoles; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D012862:Skatole; D005978:Glutathione