阿托伐他汀的肝毒性机制研究

Study on the hepatotoxic mechanism of atorvastatin

目的 研究阿托伐他汀肝毒性损伤作用及机制.方法 将24只Wistar han雄鼠分为对照组和阿托伐他汀低(68.5mg/kg)、高剂量组(205.5 mg/kg),按照10 mL/kg的药液体积给药,溶媒对照组ig等体积5% CMC-Na,连续ig 28 d.检测血清中天门冬氨酸氨基转移酶(AST)、丙氨酸氨基转移酶(ALT)、碱性磷酸酶(ALP)、尿素氮(BUN)和血肌酐(CRE)的含量,HE染色观察肝组织病理.在体外,HepG2细胞经传代培养后,给予阿托伐他汀干预24 h,检测细胞存活率,丙二醛(MDA)水平、Na+-K+-ATP酶和Ca2+-Mg2+-ATP酶活性及线粒体膜电位.结果 与对照组比较,阿托伐他汀高剂量组大鼠肝细胞弥漫性肿胀,核分裂多见,部分肝细胞极性消失,排列紊乱(P<0.05).与对照组比较,阿托伐他汀高剂量组给药后血清中ALT和AST显著升高(P<0.05、0.01).在体外,与对照组比较,阿托伐他汀125、250、500 μmol/L能明显抑制细胞存活率(P<0.05、0.001).与对照组比较,阿托伐他汀500 μmol/L HepG2细胞MDA含量明显升高(P<0.01).与对照组比较,阿托伐他汀125 μmol/L能使Na+-K+-ATP酶活性增强,500 μmol/L使Na+-K+-ATP酶活性降低(P<0.001).与对照组比较,阿托伐他汀125、250、500 μmol/L均能使能使Ca2+-Mg2+-ATP酶活性降低(P<0.01,0.001).与对照组比较,阿托伐他汀125、250、500 μmol/L均能降低线粒体膜电位(P<0.001).结论 阿托伐他汀高剂量可导致肝组织损伤,其毒性作用通过破坏细胞的线粒体膜电位,抑制Na+-K+-ATP酶、Ca2+-Mg2+-ATP酶活性,细胞膜脂质过氧化,从而破坏细胞内微环境的平衡,导致细胞凋亡和坏死.

Objective To study the hepatotoxic effects and mechanism of atorvastatin.Methods A total of 24 Wistar han male rats were divided into control group,atorvastatin low dose group(68.5 mg/kg)and atorvastatin high dose group(205.5 mg/kg).The rats were ig administered with atorvastatin according to the volume of 10 mL/kg.The rats in the control group were given 5%CMC-Na with the same volume for 28 d.Serum AST,ALT,ALP,BUN,and CRE were measured 28 days later Liver histopathology was observed by HE staining.In vitro,HepG2 cells were subcultured and treated with atorvastatin for 24 h.The cell survival rate,MDA levels,Na^+-K^+-ATPase and Ca^2+-Mg^2+-ATPase activity,and the mitochondrial membrane potential were detected.Results Compared with the control group,diffuse hepatocyte swelling and mitosis were more common in the high dose group of atorvastatin,and some hepatocyte polarity disappeared and arranged disorderly(P<0.05).Compared with the control group,ALT and AST levels in highdose group after administration with atorvastatin were significantly increased(P<0.05,0.01).In vitro,compared with the control group,the cell viability rate was significantly inhibited by atorvastatin in concentration of 125,250,500μmol/L(P<0.05,0.001).Compared with the control group,the MDA content of HepG2 cells in the atorvastatin 500μmol/L group was increased significantly(P<0.01).Compared with the control group,the activity of Na+-K+-ATPase was significantly increased in the atorvastatin 125μmol/L group,and decreased in the atorvastatin 500μmol/L group(P<0.001).Compared with the control group,125,250 and 500μmol/L of atorvastatin reduced the activity of Ca^2+-Mg^2+-ATPase(P<0.01,0.001).Compared with the control group,atorvastatin 125,250 and 500μmol/L could reduce mitochondrial membrane potential(P<0.001).Conclusion Atorvastatin can lead to liver tissue damage,and its toxic effects may by inhibiting Na^+-K^+-ATPase,Ca^2+-Mg^2+-ATPase activity and increasing lipid peroxidation of cell membrane,and destroying the mitochondrial membrane potential of cells,thus damaging the balance of intracellular microenvironment and leading to cell apoptosis and necrosis.