Huijzer J C, Adams J D, Yost G S
Toxicol Appl Pharmacol. 1987 Aug;90(1):60-8. doi: 10.1016/0041-008x(87)90306-1.
The bioactivation of the pulmonary toxin 3-methylindole has been postulated to proceed via the formation of an imine methide. To test this hypothesis, the toxicity in mice of 3-methylindole has been compared to the toxicity of its perdeuteromethyl analog. Deuteration of the methyl group should slow the rate of production of the corresponding imine methide and diminish the toxicity of deutero-3-methylindole, if C-H bond breakage occurs prior to or during the rate-determining step. In agreement with this hypothesis, deutero-3-methylindole was synthesized and was shown to be significantly less toxic (LD50 735 mg/kg) than 3-methylindole (LD50 578 mg/kg). Both compounds produced the same lesion at the LD50 dose, bronchiolar damage and mild alveolar edema, indicating that deuteration of 3-methylindole did not change the pathologic process. However, at a much lower dose (25 mg/kg), 3-methylindole produced a mild bronchiolar lesion whereas deutero-3-methylindole did not damage lung tissue. Additionally, administration of deutero-3-methylindole caused less pulmonary edema compared to 3-methylindole, as assessed by increased wet lung weights. Finally, the depletion of pulmonary glutathione by deutero-3-methylindole was considerably slower than depletion by 3-methylindole. The electrophilic imine methide has been postulated to be the intermediate which binds with and depletes glutathione. Therefore, the evidence presented here supports the involvement of an imine methide as the primary reactive intermediate in 3-methylindole-mediated pneumotoxicity.
肺毒素3-甲基吲哚的生物活化过程被推测是通过亚胺甲基化物的形成来进行的。为了验证这一假设，将3-甲基吲哚在小鼠体内的毒性与其全氘代甲基类似物的毒性进行了比较。如果在速率决定步骤之前或期间发生C-H键断裂，甲基的氘代应该会减慢相应亚胺甲基化物的生成速率，并降低氘代-3-甲基吲哚的毒性。与这一假设一致，合成了氘代-3-甲基吲哚，结果表明其毒性（半数致死量735毫克/千克）明显低于3-甲基吲哚（半数致死量578毫克/千克）。两种化合物在半数致死量剂量下产生的病变相同，即细支气管损伤和轻度肺泡水肿，这表明3-甲基吲哚的氘代并没有改变病理过程。然而，在低得多的剂量（25毫克/千克）下，3-甲基吲哚产生了轻度的细支气管病变，而氘代-3-甲基吲哚并未损伤肺组织。此外，通过增加的肺湿重评估，与3-甲基吲哚相比，给予氘代-3-甲基吲哚引起的肺水肿较少。最后，氘代-3-甲基吲哚导致肺谷胱甘肽的消耗比3-甲基吲哚慢得多。亲电亚胺甲基化物被推测是与谷胱甘肽结合并使其消耗的中间体。因此，这里提供的证据支持亚胺甲基化物作为3-甲基吲哚介导的肺毒性的主要反应中间体的参与。
