Kumar Sanjay, Bandyopadhyay Uday
Division of Drug Target Discovery and Development, Central Drug Research Institute, Chatter Manzil Palace, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India.
Toxicol Lett. 2005 Jul 4;157(3):175-88. doi: 10.1016/j.toxlet.2005.03.004. Epub 2005 Apr 7.
Severe hemolysis or myolysis occurring during pathological states, such as sickle cell disease, ischemia reperfusion, and malaria results in high levels of free heme, causing undesirable toxicity leading to organ, tissue, and cellular injury. Free heme catalyzes the oxidation, covalent cross-linking and aggregate formation of protein and its degradation to small peptides. It also catalyzes the formation of cytotoxic lipid peroxide via lipid peroxidation and damages DNA through oxidative stress. Heme being a lipophilic molecule intercalates in the membrane and impairs lipid bilayers and organelles, such as mitochondria and nuclei, and destabilizes the cytoskeleton. Heme is a potent hemolytic agent and alters the conformation of cytoskeletal protein in red cells. Free heme causes endothelial cell injury, leading to vascular inflammatory disorders and stimulates the expression of intracellular adhesion molecules. Heme acts as a pro-inflammatory molecule and heme-induced inflammation is involved in the pathology of diverse conditions; such as renal failure, arteriosclerosis, and complications after artificial blood transfusion, peritoneal endometriosis, and heart transplant failure. Heme offers severe toxic effects to kidney, liver, central nervous system and cardiac tissue. Although heme oxygenase is primarily responsible to detoxify free heme but other extra heme oxygenase systems also play a significant role to detoxify heme. A brief account of free heme toxicity and its detoxification systems along with mechanistic details are presented.
在病理状态下发生的严重溶血或肌溶解，如镰状细胞病、缺血再灌注和疟疾，会导致高水平的游离血红素，从而产生不良毒性，导致器官、组织和细胞损伤。游离血红素催化蛋白质的氧化、共价交联和聚集体形成，并将其降解为小肽。它还通过脂质过氧化催化细胞毒性脂质过氧化物的形成，并通过氧化应激损伤DNA。血红素作为一种亲脂性分子插入膜中，损害脂质双层和细胞器，如线粒体和细胞核，并使细胞骨架不稳定。血红素是一种强效溶血剂，可改变红细胞中细胞骨架蛋白的构象。游离血红素会导致内皮细胞损伤，引发血管炎症性疾病，并刺激细胞内粘附分子的表达。血红素作为一种促炎分子，血红素诱导的炎症参与多种疾病的病理过程，如肾衰竭、动脉硬化、人工输血后并发症、腹膜子宫内膜异位症和心脏移植失败。血红素对肾脏、肝脏、中枢神经系统和心脏组织具有严重的毒性作用。虽然血红素加氧酶主要负责清除游离血红素，但其他额外的血红素加氧酶系统在清除血红素方面也发挥着重要作用。本文简要介绍了游离血红素毒性及其解毒系统，并阐述了其作用机制。
