呋喃妥因在肝细胞中的氧化还原循环诱导的溶酶体氧化应激细胞毒性。

Lysosomal oxidative stress cytotoxicity induced by nitrofurantoin redox cycling in hepatocytes.

作者信息

Pourahmad J, Khan S, O'Brien P J

机构信息

Faculty of Pharmacy, University of Toronto, ON, Canada.

出版信息

Adv Exp Med Biol. 2001;500:261-5. doi: 10.1007/978-1-4615-0667-6_41.

DOI:10.1007/978-1-4615-0667-6_41

Abstract

The enzymes responsible for the reductive activation of NFT are not known. We have now shown that under aerobic conditions, inhibitors of cytochrome P450 or P450 reductase but not DT diaphorase prevented NFT induced cytotoxicity and reactive oxygen species ("ROS") formation. This suggests that NFT was reductively activated by reduced cytochrome P450 and/or P450 reductase. 2. The subcellular organelle oxidative stress effects leading to cytotoxicity are not known. Hepatocyte mitochondrial membrane potential was only slightly decreased by NFT before cytotoxicity ensued. However NFT induced lysosomal damage and hepatocyte protease activation. Endocytosis inhibitors, lysosomotropic agents or lysosomal protease inhibitors also prevented NFT induced cytotoxicity. 3. Lipid peroxidation also preceded cytotoxicity. Furthermore desferoxamine (a ferric chelator), antioxidants or ROS scavengers (catalase, mannitol, TEMPOL or dimethylsulfoxide) prevented NFT cytotoxicity. 4. It is concluded that H2O2 reacts with lysosomal Fe(+2) to form "ROS" which causes lysosomal lipid peroxidation, membrane disruption, protease release and cell death.

摘要

负责NFT还原激活的酶尚不清楚。我们现已表明，在有氧条件下，细胞色素P450或P450还原酶的抑制剂可阻止NFT诱导的细胞毒性和活性氧（“ROS”）形成，但DT黄递酶抑制剂则无此作用。这表明NFT是由还原型细胞色素P450和/或P450还原酶还原激活的。2. 导致细胞毒性的亚细胞器氧化应激效应尚不清楚。在细胞毒性出现之前，NFT仅使肝细胞线粒体膜电位略有下降。然而，NFT可诱导溶酶体损伤和肝细胞蛋白酶激活。内吞抑制剂、溶酶体促渗剂或溶酶体蛋白酶抑制剂也可阻止NFT诱导的细胞毒性。3. 脂质过氧化也先于细胞毒性出现。此外，去铁胺（一种铁螯合剂）、抗氧化剂或ROS清除剂（过氧化氢酶、甘露醇、TEMPOL或二甲基亚砜）可阻止NFT的细胞毒性。4. 得出的结论是，H2O2与溶酶体中的Fe(+2)反应形成“ROS”，后者导致溶酶体脂质过氧化、膜破坏、蛋白酶释放和细胞死亡。