Yost G S, Kuntz D J, McGill L D
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City.
Toxicol Appl Pharmacol. 1990 Mar 15;103(1):40-51. doi: 10.1016/0041-008x(90)90260-2.
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.
高剂量（550毫克/千克）的3-甲基吲哚（3MI）特异性损伤了瑞士 Webster 小鼠的肺组织，而未引起任何肝或肾坏死。当在低剂量3-甲基吲哚（75毫克/千克）给药前3小时给小鼠施用谷胱甘肽耗竭剂L-丁硫氨酸-（S，R）-亚砜亚胺（BSO，1.0毫摩尔/千克）时，4小时后通过组织病理学检查观察到明显的肾损伤。肾毒性发生时肺组织没有任何可观察到的病理损伤。增加BSO剂量会导致肾毒性呈剂量依赖性增加。低剂量的BSO（1.0毫摩尔/千克）不会导致肾谷胱甘肽水平降低，会导致肝谷胱甘肽水平大幅降低（降至对照值的60%），并且[甲基-14C]3-甲基吲哚与肾组织的共价结合增加幅度（3.4倍）远大于与肝组织（1.5倍）或肺组织（2.1倍）的增加幅度。在任何剂量的BSO与75毫克/千克3MI组合使用时，均未观察到肝或肺组织病理学损伤的证据。这些结果表明，由于肝组织中谷胱甘肽的消耗，3MI诱导的毒性的器官选择性从肺转移到了肾。在谷胱甘肽耗竭的小鼠肝脏中产生的一种有毒代谢物循环到易感肾细胞，可能是3MI这种有趣的毒性器官选择性转移的机制。
