自由基与青蒿琥酯毒性机理

Free radicals and mechanism of toxicity of sodium artesunate

本文报道用电子自旋共振波谱法测定青蒿琥酯在体内、外代谢转化过程中产生的自由基;用硫代巴比妥酸法测定静脉注射该药后大白鼠的肝、肠组织内丙二醛含量的变化;及用光学和电子显微镜观察维生素E对该药所致肝肠病理变化。结果表明青蒿琥酯在体内、外代谢过程中均可产生自由基,并可引发脂质过氧化和组织损伤。使用抗氧化剂维生素E可以抑制该药自由基的产生并减轻脂质过氧化,免除组织损伤。据此认为青蒿琥酯的主要毒性作用机理之一,可能是该药在代谢过程中产生的自由基攻击不饱和脂肪酸,引发脂质过氧化,导致细胞膜结构损伤和细胞功能紊乱,从而表现出其毒性作用。

Sodium artesunate (SA)is a water soluble antimalaria drug.In view of its unique structure (new sesquenterpenelactone)and some biological characters such as having a very short half life (t1/2=25.2 min in dog),loss of its peroxy group during metabolism,but its toxic action runing a very long sustained course,showing a centrol zone hepatic injury,and damage to membrane structure of the cells,the elaboration of free radicals resulting in lipid peroxidation (LPO)is suspected to be the likely mechanism of the toxicity of this drug.In this paper,the malondialdehyde (MDA),a product of decomposition of polyunsaturated fatty acids was detected with thiobarbituric acid test (TBA)at different doses and time interval in rats treated with SA.The results showed that there was positive correlation between dose of SA and level of MDA,r = 0.9470 and 0.9659 for liver ad small intestine respectively.The level of MDA rose up significantly 6 h after single iv SA 333 mg/ kg and lasted for 144 h in both tissues.Liver and small intestine were taken for electron spin resonance (ESR)survey at 77°K 30 min after iv SA 333 mg / kg.The spectra of free radicals obtained from these tissues were more obviously than that fromNaHCO3 control.Its G value was 2.019 that meant a peroxy radical.In vitro,rat liver microsome preparation incubatinng with SA,HADPH,and tNB at 37℃ for 30 min produced the spectra of tNB-free radical adducts.This meant that SA could form free radicals during its metabolism both in vivo and in vitro.The damage of cellular components such as nuclear membrane,endoplasmic reticulum,mitochondria etc was observed with electron microscope (EMS)at 0.5 and 24 h after administration of SA.Vitamin E was used to scavenge the free radical formed in SA metabolism.It inhibits the MDA came from lipid peroxidation (LPO)in rat also.Vitamin E can protect the structure of cells from being injured by SA.Thus it is suspected that one of the mechanisms of SA toxicity may be that SA produces free radicals during its metabolism in body.The free radicals induce lipid peroxidation of polyunsaturated fatty acids to form lipid free radicals.LPO damage the function and structure of cells.Vitamin E is effective to protect the cells from injury.